COVID-19 myocarditis and lasting heart damage: is deregulation of the Beclin1-Survivin axis the critical step of pathogenesis?

Abstract

The COVID-19 pandemic, caused by the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infection poses a serious threat for the heart [1,2]. Myocardial damage has been observed in a large percentage of hospitalized COVID-19 patients and has been related to a poor prognosis [1]. Moreover, COVID-19 survivors have been reported to develop late-onset cardiovascular sequelae with myocarditis-like changes detected by cardiovascular magnetic resonance (CMR) [1–4]. It has been observed that about 80% of patients affected by severe COVID-19 show cardiac involvement and nearly 25% presents with ongoing myocardial inflammation three months after diagnosis [3]. It is still controversial whether COVID-19 myocarditis is due to direct SARS-CoV2 injury or secondary immune reactions [1–4]. The long-term impact of COVID-19 myocarditis and the mechanisms and the degree of the myocardial damage still remain unclear [1–4]. Emerging evidence suggests an important role of autophagy in SARS-CoV2 infection [5]. Similarly to Middle East Respiratory Syndrome – Coronavirus (MERS-CoV), SARS-CoV2 has been detected to casually recruit autophagy for its replication and spread [5,6]. It has been shown that SARS-CoV2 triggers incomplete autophagy by interacting with Beclin1 to negatively regulate antiviral innate immunity and promote viral escape and replication [5–7]. Autophagy represents a cellular machinery necessary for maintaining cellular homeostasis in virtually all types of cells [5,6]. Autophagy plays a pivotal role in controlling viral replication and antiviral immune responses [6]. Beclin1 protein represents a hallmark of autophagy [8]. Autophagy is also crucial to preserve cellular homeostasis in the heart exerting a cardio-protective action against external stress [8]. Deregulation of Beclin1 has been linked to the pathogenesis of many human heart conditions such as ischemia–reperfusion injury, myocardial infarction, cardiac hypertrophy and heart failure [8]. In addition to autophagy, Beclin1 has been involved in the regulation of other biological processes including apoptosis suggesting that the autophagic and apoptotic machineries may be functionally connected and cross-talked [8– 10]. Beclin1 has been found to interact with survivin [9]. Survivin is the smallest member of inhibitor of apoptosis protein family [9]. Survivin appears to inhibit cell apoptosis and promote proliferation [9]. It has been found that upregulation of survivin is accompanied by an elevation of the key components of autophagy pathway including Beclin1 [10]. It has been verified that knockdown of Beclin1 down-regulates survivin and the turnover rate of survivin is increased when Beclin1 expression is silenced [11]. Although up-regulation of survivin in neoplastic diseases represents an unfavorable prognostic factor correlating with resistance to apoptosis in cancer cells, survivin expression has been demonstrated to be a mechanism by which cardiomyocytes at risk of apoptosis preserve their viability [10,11]. Survivin myocardial expression after myocardial infarction (AMI) has been associated with the survival of at risk myocardium and a more favorable remodeling after AMI [11]. Survivin gene therapy has also been found to lessen left ventricular systolic dysfunction in doxorubicin cardiomyopathies by reducing apoptosis and fibrosis [12]. In vitro and in vivo it has been provided evidence that there is a connection between the pro-inflammatory cytokine Interferonγ (IFN-γ) and activation of Beclin1 [13]. IFN-γ has been implicated in the pathogenesis of a number of forms of heart diseases including viral myocarditis [14]. It has been highlighted that the inflammation that is connected with up-regulation of IFN-γ often continues for months or years after the clearance of infection in the myocardium [14]. Interestingly, it has been proposed that persistent myocardial inflammation resulting in incomplete recovery may be due to a post-COVID-19 autoimmune response [1]. Notably, it has been recognized that IFN-γ represents an independent risk factor linked to mortality in patients with moderate to severe COVID-19 infection [15]. It has been proved that IFN-γ is significantly more expressed in COVID-19 patients when compared with controls increasing over time in critically ill COVID-19 patients [15]. All these contentions led me to suggest that there is a need for careful evaluation of recovered patients with COVID-19 myocarditis because delayed onset of cardiovascular sequelae may be a possibility in COVID-19 survivors. I am the first to hypothesize that SARS-CoV2 may cause the hijacking of the Beclin-1/survivin signaling axis leading to long lasting heart injury (Figure 1). I suppose that SARS-CoV2 may lead to depletion of Beclin1 and thereby survivin levels to support viral replication, transmission, or escape from immunity resulting in knocking down the major restorative processes underlying protection from cardiac injury. I also hypothesize that SARS-CoV2 induces upregulation of IFN-γ, which, in turn increases Beclin1 expression and further facilitates SARS-CoV-2 cell entry and infectivity. I assume that COVID-19 may directly cause chronic heart damage both by down-regulation of Beclin1/survivin signaling pathway and indirectly by persistence of higher serum IFN-γ levels after the clearance of SARS-CoV2 in the myocardium. Thus, I advise that targeting the Beclin1/survivin axis may represent an interesting