High degree atrioventricular block and COVID-19 infection: a two player match?

KEYWORDS:

• COVID-19
• TBX3
• TGF-beta1
• high degree atrioventricular block
• arrhythmias
• scn5A

High degree atrioventricular block has been recently reported as possible complication in Coronavirus disease-19 (COVID-19) hospitalized patients with no previous history of arrhythmias and without necessarily showing a severe inflammatory profile [1–4]. COVID-19 represents a widespread international health threat transmissible through the severe acute respiratory syndrome coronavirus 2 (SARSCoV2) [4–7]. Although COVID-19 is mainly a respiratory disease, it has been shown to affect various and differing organ systems including the heart and the cardiovascular conduction system [8,9]. Currently available evidence has also shown that there may be a lasting impairment of the cardiac function in patients who have recovered from COVID-19 [9]. Cardiac arrhythmias have been widely described in patients with COVID-19 [1,3]. COVID-19 infection have been found to disrupt almost all sites of the cardiac conduction [5,6]. Different types of atrioventricular (AV) nodal block, including high-degree AV and complete heart block have been identified [1–6]. The majority of cases of high degree AV block have been documented to be generally transient and self-resolving [4–6]. However, cases of persistent complete heart block following COVID-19 infection, requiring either permanent and/or temporary, pacemaker (PPM) insertion with mostly a preserved left ventricular ejection fraction (LVEF), have been well documented [5,6]. To date, the exact underlying mechanism belonging COVID-19 to varying degrees of AV node dysfunction still remains to be clarified [1–6]. A severe systemic inflammatory burden or a potential direct viral injury to the heart with local inflammation leading to myocardial damage or a side effects of drug therapies and interactions have been indicated among the possible causes of high degree AV block in the setting of COVID-19 infection without any conclusive evidence [3,6]. Cytokines have been recognized to be involved in the pathogenesis of COVID-19 [8]. It has been shown that COVID-19 infection triggers an acute overproduction and uncontrolled release of pro-inflammatory markers, referred to as cytokine storm, leading to corresponding pathogenic clinical manifestations resulting in multiple organ damage [8,9]. The severe inflammatory response during COVID-19 infection has been proposed to permanently impair cardiac conduction system leading to a complete AV node block [3]. Recent data have been providing evidence for a link between interleukin-6 (IL-6) elevation, cardiac connexin-43 downregulation and acute and reversible atrioventricular delay during active systemic inflammatory processes [10]. However, the mechanistic pathway linking systemic inflammation to atrioventricular block via IL-6-mediated inhibition of connexin-43 expression would not seem to apply to COVID-19 patients [10]. Recently, it has been reported that upregulation of connexin-43 hemichannels, being key players in inflammation, can be involved in the initiation an dissemination of inflammatory processes connected with COVID-19 pathogenesis, so much so that the effects of drugs formerly designated for COVID-19 therapy on connexin-43 hemichannels have been investigating [11]. It has been argued that features of cytokine storm and pathogenesis of COVID-19 are associated with the imbalanced cytokine network due to an aberrant increase in Transforming Growth Factor beta (TGF-β) activity [9]. In this light, TGF-β has been defined as the main component of cytokine storm resulting from SARSCoV2 infection [9]. TGF-β represents a multifunctional and pleiotropic cytokine with an important role in the repairing process and suppression of immune response [9,12]. Among the three isoforms of TGF-β, β1-β3, TGF-β1 is mainly implicated in the immune regulation [12]. It has been suggested that TGF-β induction is a significant contributor to the short and long-term effects of COVID-19 infection [9,12]. It has been highlighted that there is a crucial raise in the serum levels of TGF-β1 in samples from patients with COVID-19 of any types of severity [13]. Intriguingly, it has been demonstrated that SARSCoV2 in severe COVID-19, causes a TGF-β-controlled chronic immune response which is no longer directed to itself implying an inefficient immune reaction to SARSCoV2 and a sustained involvement of TGF-β1 in long-term deleterious effects from COVID-19 [9,14]. TGF-β1 has been acknowledged to be a key player in cardiac myofibroblast arrhythmogenicity [15]. It has been stated that TGF-β1 significantly modifies the electrophysiological phenotype of cardiac myofibroblasts [15]. TGF-β1 signaling pathway has been proposed as a possible pivotal player in the regulation of T-box- transcription factor TBX3 [16]. TGF-β1 pathway has been verified to up-regulate TBX3 [16]. TBX3 belongs to the T-box family of transcription factors, which controls the embryonic development and postnatal function of a number of tissues [17]. TBX3 has been connected with the postnatal health of the human conduction system of the heart [17]. TBX3 has been revealed to reprogram mature cardiac myocytes into pacemaker-like cells [17]. The expression of TBX3 in adult cardiomyocytes has been proved to lead to conduction slowing by modifying the mechanism underlying spontaneous activity and, reducing the velocity of impulse propagation [17]. Patients affected by TBX3 mutations have been recommended to be followed along the time for the possibility of developing adult-onset conduction diseases such as atrioventricular block [18]. It has been provided evidence that trait-associated noncoding variant regions alter the regulation of TBX3 and the cardiac conduction [19]. TBX3 has been proved to be a candidate tissue-specific member of the β-catenin transcriptional complex [19]. TBX3 appears to be a tissue-specific component of the Wnt/β-catenin enhanceosome [20]. Wnt/β-catenin signaling pathway has been tested to have a critical role in heart development as well as in cardiac tissue homeostasis in adults by having an impact on cardiac function and dysfunctions [21]. It has been written that in specific developmental and disease contexts, TBX3 can be implicated in the direct regulation of Wnt target genes by functional interplay with the β-catenin/BCL9-dependent transcriptional complex [20]. The two paralogs BCL9 and BCL9L, located within the so-called enhanceosome, are essential to efficiently stimulate Wnt-target gene expression [20]. Canonical Wnt signaling has been evidenced to control atrioventricular (AV) junction programming and electrophysiological properties [21]. It has been corroborated that myocardial canonical Wnt signaling represents a critical regulator of AV canal maturation and electrical programming upstream of TBX3 [21]. Abnormal regulation of the Wnt/β-catenin pathway has been linked to several different types of heart diseases including arrhythmias [22]. Wnt signaling has been shown to block the Na⁺ channel by direct and indirect suppression of SCN5A gene transcription via TBX3 [23]. TBX3 is considered a suppressor of SCN5A [23]. SCN5A represents an alpha subunit (Na_v1.5) that encodes the cardiac sodium channel and contributes to the action of cardiac myocytes and the generation and transmission of bits [24]. Sodium channels are essential for the normal electrical activity of the heart and mutations in genes that encode for these channels or their associated proteins such as SCN5A trigger arrhythmogenic syndromes [25]. SCN5A gene mutation has been suggested to be implicated in the occurrence of third-degree AVB by decreasing the function of sodium channels and blocking the cardiac conduction system in variable degrees, eventually leading to the occurrence of AVB [25]. It is well known that cardiac natriuretic channels are widely present in atrial and ventricular myocytes and Purkinje fibers [25]. Ionic currents (I_Na) appear to shape the ascending branch of action potential and regulate the excitability and conduction velocity of the heart [23] Overexpression or knockdown of TBX3 have been proved to directly alter both Na_v1.5 and I_Na [23]. Taken together, I conjecture the existence of a novel level of cytokine cross-talk in the onset of high degree atrioventricular block in COVID-19 patients consisting of a synergistic interaction between TGF-β1 and TBX3 resulting in an aberrant activation of the Wnt/β-catenin pathway and loss-of-function mutations of SCN5A gene associated with decreased function of the sodium channel.fi I suppose that TBX3 gene polymorphisms may be at the basis of the increased susceptibility to high degree AV block in selected COVID-19 patients. If that is the case, I suggest that targeting TGF-β1-TBX3 axis may be explored as a potential anti-arrhythmic treatment to prevent AV block after COVID-19 infection. On this regard, I hypothesize that convalescent COVID-19 patients with persistent or transient high degree AV block should undergo blood examination with single nucleotide polymorphisms (SNPs) genotyping assay in order to identify possible inherited bradyarrhythmia susceptibility correlated to TBX3 variants of different penetrance and variable expressivity. As a final point, I advise that a prospective arrhythmia surveillance through electrocardiographic screening may be a valuable tool to stratify the risk of symptomatic and fatal arrhythmic events within the large pool of patients with a recent and confirmed COVID-19 infection, even mild or asymptomatic, during hospitalization and after their discharge, in order to promptly diagnose and implant a life-saving pacemaker, taking into account that the electrocardiogram is a very informative, inexpensive and accessible test and that it is very difficult to identify the subset of asymptomatic subjects who are at risk for high degree atrioventricular block (Figure 1).

Figure 1. HIGH DEGREE ATRIOVENTRICULAR BLOCK AND COVID-19 INFECTION: A TWO PLAYER MATCH?.

Declaration of Interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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