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Editorial

Possible molecular and paracrine involvement underlying the pathogenesis of COVID-19 cardiovascular complications

AbdelMassih, Antoine Fakhrya,,b; Ramzy, Davidc; Nathan, Laurenc; Aziz, Silviac; Ashraf, Mirettec; Youssef, Nourhan Hatemc; Hafez, Nouranc; Saeed, Ranac; Agha, Halaa,,d

Author Information
Cardiovascular Endocrinology & Metabolism: April 20, 2020 - Volume 9 - Issue 3 - p 121-124
doi: 10.1097/XCE.0000000000000207
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Abstract

Introduction

Coronavirus disease 2019 (COVID-19) is a respiratory disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). It has rapidly evolved from a small-scale epidemic involving a province in China to a worldwide pandemic with more than a million-person affected and putting the whole world in a huge lockdown state. COVID-19 is not the first outbreak caused by CoV (coronavirus), two outbreaks have occurred prior to COVID-19, namely SARS-1 and Middle East respiratory syndrome (MERS) [1].

Several reports have shown strong evidence that CoV may affect the cardiovascular system. Xiong et al. [2] summarised in his review earlier this year the reported cases of cardiovascular involvement with CoV, whether the current outbreak or the two mentioned milder versions SARS-1 and MERS. The case series reported by Xiong et al. [2] displayed several patterns ranging from sudden cardiac arrest as in the Pan et al. [3] series to subclinical involvement and chronic heart failure in the report by Li et al. [4]. Between the aforementioned extreme patterns, the predominant pattern shown is acute heart failure resulting from acute myocardial injury with subsequent elevation of cardiac enzymes specifically highly sensitive cardiac troponins as in Yu et al., Alhogbani et al., Wang et al. and Inciardi et al. series [5–8]. Direct transfection of myocardial cells has been ruled out as a cause of such myocardial involvement by a recent case report by Sala et al. In his report, Sala et al. [9] describe an acute myocardial injury pattern, where endomyocardial biopsy showed inflammatory infiltration without any molecular evidence of viral presence inside the myocardial cells. Another possible explanation of such cardiovascular complications is the heart–lung interactions. Respiratory compromise might increase pulmonary vascular resistance with subsequent right ventricular failure. However, this suggested theory cannot provide full justification of the observed cases in the published series, as some of the cases presented with cardiac involvement without any evidence of prior respiratory compromise. Moreover, heart failure was mainly due to left ventricular and to a lesser extent biventricular hypokinesis; also, respiratory compromise cannot explain the persistence of myocardial injury years after recovery from respiratory compromise as reported by Li et al. Finally, yet importantly, the marked elevation of highly sensitive cardiac troponins might raise the susceptibility of coronary involvement not only primary myocardial injury, as cardiac troponins have shown superiority in the diagnosis of cardiomyocyte injury related to defects of myocardial perfusion rather than other mechanisms. In this report, we aim to link evidences to elucidate possible mechanisms in induction of myocardial injury in the context of COVID-19. We hypothesise that the observed pattern of acute heart failure might be related to two possible mechanisms, direct myocardial injury or secondary myocardial involvement to endothelial dysfunction with subsequent impaired coronary relaxability. We also hypothesise that autocrine and paracrine mechanisms by different circulating substances lie at the core of such pathogenesis [2–8,10–15].

I-The Angiotensin pathway theory

Angiotensin-converting enzyme-2 (ACE 2) is a type I transmembrane metallocarboxypeptidase with homology to ACE, an enzyme long-known to be a key player in the renin–angiotensin system (RAS) and a target for the treatment of hypertension. It is mainly expressed in vascular endothelial cells, endocardial cells as well as the renal tubular epithelium, and in Leydig cells in the testes [16].

Angiotensin-converting enzyme-2 and myocardial protection from inflammation

ACE 2 has been shown to have protective effects on the myocardium. Qi et al. showed that upregulation of ACE is associated with better outcomes after myocardial infarction with less transmural inflammation and subsequent reduction in infarct size and better myocardial functions.

This protective effect has been shown to be mediated by high mobility group box-1. These chromatin proteins are important mediators of inflammation. Their stimulation has been shown to increase cytokine release [17].

Angiotensin-converting enzyme-2 and endothelial preservation

ACE 2 is heavily expressed in vascular endothelial cells; the vascular protective effects of ACE 2 were reported even before its myocardial protective effects. ACE 2 stimulation has been shown to attenuate atherosclerosis and to improve endothelium-dependent relaxation. ACE 2 protective effects on vascular endothelium seem to be mediated by different mechanisms than those observed in myocardial cells. ACE 2 acts through angiotensin 1-7; this protein increases the expression of endothelial nitric oxide synthase and subsequently increases the concentration of endogenous vasodilators. Angiotensin 1-7 has been also shown to decrease the concentration of reactive oxygen species and to decrease endothelial inflammation with the subsequent halting of the progression of atherosclerosis [18].

COVID 19 spike protein interaction with angiotensin-converting enzyme-2 receptors

ACE 2 has been identified as the key receptor for SARS-CoV-2 interaction with human cells. It has been postulated that transcription of the ACE 2 messenger RNA (mRNA) is silenced by the virus. These events all lead to a decrease in the levels of ACE 2. In view of the explained protective effects of ACE 2 on myocardial and endothelial cells, and in view of the effect of SARS-CoV-2 on ACE 2, we can, therefore, conclude that COVID-19 might potentially induce myocardial injury, without infecting myocardial cells either by direct inflammatory effect or through impairing coronary perfusion [19].

II-Suggested paracrine involvement through direct ACE independent pro-inflammatory effect of COVID-19 and possible myocardial and endothelial sequelae

In the last few years, an increasing body of evidence has accumulated indicating that cardiomyocytes and endothelial cells exert paracrine effects on each other. These paracrine effects are mediated through cytokines that act as local hormones with multiple effects, whether damaging or beneficial. For instance, the beneficial effects of paracrine release of cytokines have been demonstrated recently in rats after heart transplantation. Paracrine factors seem to play an important role in cardiac regeneration after heart transplantation, by inducing pleiotropic effects, including anti-inflammation, anti-apoptosis, anti-fibrosis and pro-angiogenesis. Thus, transplanted stem cells may accelerate the restoration of the injured cardiac tissue through such paracrine mediators [20].

This closely relates to our context as SARS-CoV-2 binds to toll-like receptor inducing the release of pro-interleukin-1(IL-1), which is usually inactivated by regulatory caspase enzyme, leading to the activation of inflammasome and a cytokine storm syndrome alternatively called secondary hemophagocytic lymphohistiocytosis. The latter complication is regarded as the terminal lethal effect of the virus on the human body. The interruption of the aforementioned cascade is the goal of many clinical trials of drug repurposing to tame the pro-inflammatory state observed in COVID-19. The clinical trials conducted have shown promising results regarding the use of monoclonal antibodies against interleukin-6 (IL-6) specifically. The effect of this pro-inflammatory state on the lungs has been thoroughly discussed and studied; however, the possible effects of such hypercytokinaemia on the heart require further exploration [21].

Interleukin 1, the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway interactions with cardiomyocytes:

Many clinical and experimental trials have studied the pathway of members of IL-1 family and their receptors in the pathogenesis of cardiovascular diseases. For instance, in myocardial infarction IL-1α is released from necrotic cardiomyocytes acting as an alarming sign in the post-infarction inflammatory reaction, whereas IL-1β is produced from the resident cardiomyocytes and infiltrating leucocytes. Both IL-1α and IL-1β increase apoptosis of cardiomyocytes thus aggravating the ischemic injury through systolic dysfunction. Moreover, IL-1 acts on the fibroblast through overexpression of matrix metalloproteinases (MMPs) which promote cytokine/chemokine synthesis. IL-1 delays the premature trans-differentiation of myofibroblast from fibroblast leading to reduced α-smooth muscle actin expression [22].

This was confirmed through different experiments, first on incubated rat cardiomyocytes with recombinant human IL-1Ra (anakinra) (an IL-1 receptor antagonist) reduction of apoptosis was noticed through stimulated ischaemia/reperfusion protocol. Second, in-vivo significant attenuation in the infarct size was noticed through overexpression of human IL-1Ra in transplanted rat hearts undergoing ischaemia and reperfusion [23].

Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway plays critical roles in orchestrating the of immune system, especially cytokine receptors and they can modulate the polarization of T helper cells. All seven STAT family members have been reported to be expressed in the heart and cultured cardiomyocytes and are responsible for the pathogenesis of myocardial hypertrophy and ischaemia. Based on recent laboratory studies, it was reported that the target site for STAT proteins is the prohormone angiotensinogen gene promoter.

This relationship between the RAS and STAT explains why hindering RAS activation through a specific inhibitor promotes a remarkable recovery in myocardial dysfunction. Also, cellular viral entry in COVID-19 and its inflammatory consequences could be minimised through inhibition of JAK/STAT pathway possibly through interaction with ACE 2 [24].

IL-6 interactions with the vascular endothelium

The pro-inflammatory cytokine IL-6 is produced from smooth muscle cells in tunica media of blood vessels in response to inflammatory stimulus, IL-6 is released at the site of inflammation acting as the main cytokine for all acute-phase proteins. Through interaction with its soluble receptor, soluble IL-6 receptor α (sIL-6Rα), IL-6 changes the nature of leucocyte infiltrate from polymorph nuclear neutrophils to monocytes/macrophages thus changing from acute to chronic inflammation. Moreover, IL-6 exerts stimulatory actions on B- and T-lymphocytes thus favoring chronic inflammatory responses. Based on a clinical trial performed on rat aortic vascular smooth muscle cells, proving that IL-6 overexpresses angiotensin type-1 receptor mRNA de novo synthesis and the latter results in induced production of reactive oxygen species which impair endothelial vasodilation. Playing an unexpected role in leucocyte recruitment in vivo, the complex of IL-6 and sIL-6Rα can activate endothelial cells to secrete interleukin-8 (IL-8) and monocyte chemoattractant protein inducing expression of adhesion molecules. IL-6 has a paracrine manner through two distinct mechanisms. First, a classic membrane receptor-initiated pathway and the second a trans-signaling pathway being able to induce responses even in tissues lacking IL-6 receptor. After proving the effectiveness of targeting IL-6 and its signaling in prevention and treatment of models of rheumatoid arthritis and other chronic inflammatory diseases, further studies are needed to apply this strategy on cardiovascular injuries [25].

Figure 1 summarises the suggested mechanisms by which COVID-19 targets the cardiovascular system.

Fig. 1
Fig. 1:
Summary of COVID-19 mechanisms in targeting cardiovascular system. ACE 2, angiotensin converting enzyme 2; AG 1-7, angiotensin 1-7; COVID-9, coronavirus-2019; HMB-1, high mobility box-1; IL-1, interleukin-1; IL-6, interleukin-6; JAK/STAT, janus kinase/signal transducer and activator of transcription; NO, nitric oxide.

Conclusion

In view of the above, there is evidence suggesting that SARS-CoV-2 can exert a negative effect on both the endothelium and cardiomyocytes. This effect is mainly mediated through interactions with ACE 2 and through induction of hypercytokinaemia, rather than direct transfection of cardiomyocytes. Such effect might explain the myocardial infarction-like picture with which some COVID-19 patients are diagnosed. It might also serve as a good basis for drug repurposing to treat such complications. Drug repurposing might involve the use of ACE inhibitors as such inhibition has been shown to upregulate the protective ACE 2, or the use of monoclonal antibodies against either IL-1 or IL-6. Clinical trials specifically in patients with COVID-19 are required to quantify the benefits and risks of putative therapies [26,27].

Acknowledgements

As a first author would like to dedicate this paper to my mother Isis Zakarya Wahba, she taught me during my early years of life to observe, and she used always to tell me during my early career that creation of science is a matter of observation; as a good observation of a gap is all what it takes to bridge this gap. We also want to thank Prof. Andrew Krentz, the Editor-in-Chief of Cardiovascular Endocrinology and Sarah Booth the managing Editor for their great efforts to timely publish this work. We wanted also to thank every intern and student at Kasr Al Ainy Medical College as their enthusiasm is incredibly encouraging us. We want to acknowledge Dr. Nadine El-Hussieny and her graphic design company Pixagon for their efforts in improving the artwork in our Editorial. A thank you goes as well to the members of Research Accessibility Team notably: Peter Afdal, Habiba-Allah Ismail, Rahma Menshawey and Essraa Menshawey for their relentless efforts in mentoring students in Research work. Finally, yet importantly, we dedicate this work to the soul of Prof. Hala Hamza, the former head of the Pediatric Cardiology Unit, Prof. Fatma Al-Zahraa, the head of echocardiography unit in Cairo University Children Hospital and and to each and every healthcare staff (doctors, nurses and workers) who are in the frontline of the world battle against COVID.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

angiotensin-converting enzyme 2; coronavirus disease 2019; cardiomyocytes; drug repurposing; endothelium; paracrine effect of cytokines

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