To the editor,
In the beginning, the famous saying of Imam Ali said, “Two are insatiable: a seeker of knowledge and a seeker of money.“ That is why we started writing this letter, because we are seekers of knowledge.
It has been shown that 20% of COVID-19 patients had signs of acute cardiac injury (ACI) as measured by high-sensitive troponin [1]. Even after controlling for confounding factors, COVID-19-induced ACI is associated with a fourfold increase in mortality [1].The underlying mechanism for ACI in COVID-19 is related to a higher expression of angiotensin converting enzyme 2 (ACE2) in cardiomyocytes than other tissues, which is exploited by SARS-CoV-2 for entry into the host cells [2]. SARS-CoV-2 spike protein binds to ACE2 causing down-regulation of this receptor [2]. ACE2 has a protective effect on cardiomyocytes by reducing angiotensin II (AngII)-induced cardiac fibrosis, hypertrophy, and diastolic dysfunction [11]. Recombinant ACE2 reduces AngII and pressure overload-induced myocardial remodeling [11]. Therefore, ACE2 is regarded as a crucial negative regulator of AngII-induced cardiac disease and complications.
Therefore, the direct cytopathic effect of SARS-CoV-2 may lead to direct ACI in COVID-19 [2]. However, hyperinflammation, exaggerated immune response, and the development of cytokine storm could be the possible pathway for indirect ACI in COVID-19 [2].
Pharmacological therapy of ACI in COVID-19 is essential to prevent heart failure and cardiac fibrosis. In general, cardiac ischemia, heart failure, thrombotic disorders, and other cardiovascular complications in COVID-19 are treated with standard treatment approaches [3]. Colchicine, renin inhibitors, aldosterone receptor antagonists, and the neprilisin inhibitor sacubitrile have been shown to be effective in the treatment of ACI in COVID-19 [3].
Trimetazidine (TMZ), an anti-anginal agent, inhibits β-oxidation of fatty acids by blocking long-chain Acetoacetyl-CoA thiolase (thiolase II), leading to enhancement of glucose oxidation by cardiomyocytes [4]. Through energy preservation, TMZ improves cellular homeostasis and prevents intracellular reduction of adenosine triphosphate (ATP) [4]. Also, TMZ is effective against cardiac fibrosis and ischemic-reperfusion injury through modulation of cardiac fibroblast activity and the Akt/caspase-3 signaling pathway, respectively [4]. Therefore, TMZ might be effective in the management of acute coronary syndrome and other ischemic events in COVID-19 [5]. Additionally, inhibitors of fatty acid oxidation impair SARS-CoV-2 entry and replication [6]. Thus, TMZ through inhibition of the β-oxidation of fatty acids may attenuate the pathogenesis of SARS-CoV-2 infection.
Remarkably, TMZ has anti-inflammatory and antioxidant effects by inhibiting activation of nuclear factor kappa B (NF-κB) and production of reactive oxygen species (ROS) [7]. Therefore, TMZ exerts a cardio-protective effect through attenuation of mitochondrial dysfunction, inflammation, oxidative stress, and apoptosis [7]. As well, nuclear factor erythroid related factor 2 (Nrf2) which is the main transcription factor of the antioxidant mechanism, is stimulated by TMZ [7]. Indeed, induction of oxidative stress and activation of NF-κB signaling pathway are linked with ACI in COVID-19 [8]. Thus, TMZ could be effective against ACI in COVID-19 through activation of Nrf2 and suppression of NF-κB signaling pathway.
Recently, Wu et al. found that TMZ is effective against viral myocarditis because of its anti-inflammatory and immunomodulatory effects [9]. TMZ reduces cardiac inflammation in heart failure by inhibiting release of pro-inflammatory cytokines interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) [10].
Taken together, in virtue of its anti-inflammatory and antioxidant effects, TMZ might be a proposed drug for the management of ACI in COVID-19. In this regard, experimental, preclinical, and clinical studies are warranted.
Funding
No specific funding was received.
Conflict of interest
The authors have no conflicts of interest to declare.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Hayder M. Al-kuraishy, Email: hayderm36@yahoo.com
Ali I. Al-Gareeb, Email: dr.alialgareeb78@yahoo.com
Nermeen N. Welson, Email: nermeennemr@yahoo.com
Gaber El-Saber Batiha, Email: gaberbatiha@gmail.com.
References
- 1.Onohuean H, Al-Kuraishy HM, Al-Gareeb AI, Qusti S, Alshammari EM, Batiha GE. Covid-19 and development of heart failure: mystery and truth. Naunyn Schmiedebergs Arch Pharmacol. 2021;394(10):2013–21. doi: 10.1007/s00210-021-02147-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol. 2020;5(7):802–10. doi: 10.1001/jamacardio.2020.0950. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Al-Kuraishy HM, Al-Gareeb AI, Qusty N, Cruz-Martins N, Batiha GE. Sequential doxycycline and colchicine combination therapy in Covid-19: The salutary effects. Pulm pharmacol therapeut. 2021;67:102008. doi: 10.1016/j.pupt.2021.102008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Huang Q, Deng X, Li Y, Sun X, Chen Q, Xie M, et al. Clinical characteristics and drug therapies in patients with the common-type coronavirus disease 2019 in Hunan, China. Int J Clin Pharm. 2020;42(3):837–45. doi: 10.1007/s11096-020-01031-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Salinas P, Travieso A, Vergara-Uzcategui C, et al. Clinical profile and 30-day mortality of invasively managed patients with suspected acute coronary syndrome during the COVID-19 outbreak. Int Heart J 2021:20–574. [DOI] [PubMed]
- 6.Williams CG, Jureka AS, Silvas JA, et al. Inhibitors of VPS34 and fatty-acid metabolism suppress SARS-CoV-2 replication. Cell Rep. 2021;36(5):109479. doi: 10.1016/j.celrep.2021.109479. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Zhang H, Liu M, Zhang Y, et al. Trimetazidine attenuates exhaustive exercise-induced myocardial injury in rats via regulation of the Nrf2/NF-κB signaling pathway. Front Pharmacol. 2019;10:175. doi: 10.3389/fphar.2019.00175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Knowlton KU. Pathogenesis of SARS-CoV-2 induced cardiac injury from the perspective of the virus. J Mol Cell Cardiol. 2020;147:12. doi: 10.1016/j.yjmcc.2020.08.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Wu K, Deng D, Yu B, et al. Evaluation of the Efficacy and Safety of Chinese Herbal Injection Combined With Trimetazidine for Viral Myocarditis: A Network Meta-Analysis. Front Pharmacol 2021;12. [DOI] [PMC free article] [PubMed]
- 10.Shu H, Peng Y, Hang W, et al. Trimetazidine in heart failure. Front Pharmacol 2021:1753. [DOI] [PMC free article] [PubMed]
- 11.Zhong J, Basu R, Guo D, Chow FL, Byrns S, Schuster M, Loibner H, Wang XH, Penninger JM, Kassiri Z, Oudit GY. Angiotensin-converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction. Circulation. 2010;122(7):717–28. doi: 10.1161/CIRCULATIONAHA.110.955369. [DOI] [PubMed] [Google Scholar]