Anti-Ro/SSA Antibodies and the Autoimmune Long-QT Syndrome

Introduction

The long QT-syndrome (LQTS) is a cardiac electric disorder characterized by an abnormal prolongation of the heart rate-corrected QT interval (QTc) on the electrocardiogram (traditionally >440 ms; currently, >470 ms for men, and >480 ms for women) (1) which predisposes to life-threatening ventricular arrhythmias (VAs), specifically Torsades de Pointes (TdP) (1–3). TdP is a polymorphic ventricular tachycardia presenting with a typical pattern of twisting points that can rapidly degenerate into ventricular fibrillation (VF) and cause sudden cardiac death (SCD) (1). The more the QT prolongs the more the risk of TdP increases, it becoming high for QTc > 500 ms, very high for QTc > 600 ms (1). In addition, accumulating evidence indicates that when QT interval prolongs as the result of the specific lengthening of the terminal component of the T wave, from the peak to its end (Tpeak-Tend interval, Tp-Te), the risk to develop TdP is particularly important (4, 5).

The QTc on the electrocardiogram (ECG) is commonly used in the clinical practice as a proxy of the average action potential duration (APD) in ventricular cardiomyocytes, in turn determined by the sequential activation of several ion channels mediating inward depolarizing (sodium, Na⁺ and calcium, Ca⁺⁺) or outward repolarizing (potassium, K⁺) currents, respectively (6). Whenever a dysfunction of one or more of these channels occurs leading to a net inward shift in the balance of currents (i.e., an increase of Na⁺ or Ca⁺⁺ currents and/or a decrease of K⁺ currents), APD prolongs and, therefore, the QTc (6, 7). A wide number of etiologic factors can be responsible for LQTS, classically categorized as congenital, due to mutations in genes encoding for K⁺, Na⁺, or Ca⁺⁺ channels and related regulatory proteins, or acquired (8, 9). While inherited forms are relatively rare, with an estimated prevalence of ~1:2,000 of apparently healthy newborns (8, 10), acquired LQTS is a quite frequent finding (11, 12), more commonly due to medications blocking the human ether-à-go-go related gene K⁺ channel (hERG-K⁺) carrying the rapidly activating component of the delayed outward-rectifying current (I_Kr), or electrolyte imbalances (hypokalaemia, hypocalcaemia, hypomagnesemia) (1, 9). Other well-defined causes of acquired LQTS include structural heart diseases, bradyarrhythmias, liver and endocrine diseases, nervous system injuries, starvation, hypothermia, and toxins (9, 13). Although wide, this list of “conventional” risk factors is not able to account for all cases of LQTS/TdP occurrence (and recurrence) in the clinical practice (4) and for this reason in the recent years, intensive investigations were undertaken to identify previously unrecognized risk factors. As a result, an increasing number of novel, “non-conventional” QT-prolonging risk factors for acquired LQTS have been recently recognized, including human immunodeficiency virus infection (14), male hypogonadism (15, 16), heart failure with preserved ejection fraction (17), QT-prolonging foods (18), inflammation and autoimmunity (19, 20).

Regarding the autoimmune LQTS, the most investigated form is associated to the presence of circulating anti-Ro/SSA-antibodies, responsible for one of the first identified arrhythmogenic autoantibody-induced channelopathies (autoimmune cardiac channelopathies) (19, 21, 22). In fact, accumulating evidence exists that anti-Ro/SSA-antibodies exert significant electrophysiological effects on the heart via an inhibitory cross-reaction with the extracellular pore region of the hERG-K⁺ channel (23–27), leading to a higher propensity of developing LQTS (28–31) and VAs/TdP (24, 32, 33) in anti-Ro/SSA-antibody positive adults and newborns subjects. In this review, we highlight the current knowledge on this autoimmune associated LQTS form providing complementary basic, clinical and population health perspectives.

Anti-Ro/SSA-Antibodies

Anti-Ro/SSA-antibodies, comprising the anti-Ro/SSA-52kD and anti-Ro/SSA-60kD sub-specificities, result from an autoimmune response against the two subunits of the intracellular ribonucleoprotein Ro (Ro52-kD and Ro60-kD) (34). They are polyclonal antibodies, usually of the IgG class, commonly found in patients with autoimmune diseases (AD) and beyond (34–36). In particular, anti-Ro/SSA-positivity is frequent in connective tissue diseases (CTD), primarily Sjögren's syndrome and systemic lupus erythermatosus (SLE) (34). In these disorders, anti-Ro/SSA-60kD sub-specificity has a more established direct pathogenic role than anti-Ro-52kD in the development of classical autoimmune manifestations (37, 38), also being associated with a higher prevalence of extraglandular features, especially vasculitis, and greater systemic activity (39, 40). Indeed, large studies have demonstrated that anti-Ro/SSA-antibodies can be also detected in a significant proportion of subjects of the general population (0.5-2.7%) (41–43), who are in most cases (60%) asymptomatic for AD (43), particularly when anti-Ro/SSA-52kD positivity occurs alone (44).

Large evidence exists that the trans-placental passage of anti-Ro/SSA-antibodies from the mother to the fetus causes the autoimmune-congenital heart block (aCHB) (45), a paradigmatic form of passively acquired autoimmunity (46, 47). Although the pathogenesis of this disorder is complex and only in part elucidated, many clinical and experimental data have demonstrated that an inhibitory cross-reaction between anti-Ro/SSA-antibodies and the L- and T-type Ca⁺⁺-channels in fetal conduction system cardiomyocytes plays a key mechanistic role (48–54).

In the clinical practice, several laboratory methods are available for anti-Ro/SSA-antibody detection, the more commonly used being immunoenzymatic tests (ELISA, FEIA) and line-blot immunoassay (LIA), all based on recombinant Ro antigens use as substrate (34, 36, 55, 56). However, increasing evidence indicates that immuno-Western blot (iWB), using the native Ro antigen, is the most sensitive technique to reveal anti-Ro/SSA-positivity in the general population (36) as well as arrhythmogenic autoantibodies in aCHB (57), more frequently being identified as the anti-Ro/SSA-52kD subtype (57).

Anti-Ro/SSA-Associated Long-QT Syndrome

Clinical Data

The first studies showing an association between anti-Ro/SSA-antibodies and LQTS were performed in children in the early 2000s (Table 1). Cimaz et al. (28) reported that newbors/infants without aCHB from anti-Ro/SSA-positive mothers had longer QTc than anti-Ro/SSA-negative controls. Moreover, the same authors demonstrated that such alteration normalized spontaneously during the first year of life together with the disappearance of maternally-acquired anti-Ro/SSA-antibodies, thereby pointing to a functional and reversible interference on ventricular repolarization (59). Later, four independent groups provided data further supporting this association (Table 1). Gordon et al. (58) demonstrated that QTc was significantly prolonged in children from anti-Ro/SSA-positive mothers when compared to those from anti-Ro/SSA-negative mothers, with a more marked prolongation in siblings of a child with aCHB. Then, Jaeggi et al. (60) reported that in a Canadian cohort 116 anti-Ro/SSA-positive newborns/infants without aCHB, transient QTc prolongation was rather frequent, it being present in 15% of cases (60). Consistent data were more recently obtained by Friedman et al. (62) who analyzed the ECGs of 45 infants without aCHB born from anti-Ro/SSA-positive mothers and found that QTc prolongation > 2 standard deviations above historical healthy controls was present in 11% of subjects. Moreover, AlTwajery et al. (61) demonstrated that among 41 children affected with SLE, anti-Ro/SSA-positivity was associated with a higher prevalence of ECG abnormalities, particularly QTc prolongation > 450 ms. Finally, three cases of marked QTc prolongation complicated with ventricular tachycardia/TdP in infants from anti-Ro/SSA-positive mothers with aCHB are reported (63–65).

TABLE 1

Table 1. Clinical studies showing an association between anti-Ro/SSA antibodies and QTc/TdP.

In agreements with these findings, several studies demonstrated an increased prevalence of QTc prolongation and VAs in adults with circulating anti-Ro/SSA-antibodies (Table 1). Our group was the first to provide evidence that anti-Ro/SSA-positive adults with CTD frequently show QTc prolongation (>440 ms in ~45-60% of cases) (29, 32), persisting throughout the 24 h and correlating with the risk of complex VAs (32). Later on, Bourré-Tessier et al. (30) conducted two consecutive studies on a larger cohort of SLE patients where anti-Ro/SSA-positivity was found to be associated with a 5-12-times higher incidence of QTc prolongation, with a correlation with autoantibody levels. This latter finding was confirmed and refined by our group, by demonstrating that only the serum concentration of the anti-Ro/SSA-52kD subtype significantly and specifically associated with QTc duration (66).

After these seminal studies, many other authors provided clinical evidence supporting the existence of a relationship between anti-Ro/SSA-antibodies and QTc prolongation risk in adults (Table 1). Pisoni et al. (67) demonstrated that among 73 AD patients, the prevalence of QTc > 440 ms was significantly higher in anti-Ro/SSA-positive (20%) vs. –negative subjects (0%). Consistent results were obtained by four subsequent studies, all conducted in SLE patients. Sham et al. (68) reported that mean QTc was longer in SLE subjects with, rather than without circulating anti-Ro/SSA-antibodies, while Mostafavi et al. (71) and Perez-Garcia et al. (69) found that anti-Ro/SSA-antibodies were more commonly detectable and at a higher concentration when SLE patients with QTc prolongation were compared to those with a normal QTc. Moreover, in a study using machine learning in 299 patients with SLE, Hu et al. (72) identified anti-Ro/SSA positivity as one of the most important independent variables associated with QTc prolongation > 450 ms in these subjects. Regarding the specific role of the anti-Ro/SSA-52kD subtype, Tufan et al. (70) reported increased QTc maximum and Tp-Te values in anti-Ro/SSA-52kD-positive CTD patients in comparison to negative patients and healthy controls. In addition, Perez-Garcia et al. (69) and Tufan et al. (70) found that anti-Ro/SSA-52kD levels were significantly associated with QTc and Tp-Te duration in SLE and CTD patients, respectively.

Further studies provided evidence that anti-Ro/SSA-antibodies, regardless of the presence or absence of a clinically evident CTD/AD, are per se associated with LQTS/TdP (Table 1). This is a very important point, as it intriguingly suggests that these autoantibodies may represent a concealed risk factor possibly contributing to life-threatening VAs/SCD events in the general population (21). In fact, after the early case report by Nakamura et al. (33) of recurrent TdP episodes in an otherwise healthy anti-Ro/SSA-positive woman with circulating anti-Ro/SSA-antibodies, our group more in general demonstrated that circulating anti-Ro/SSA-antibodies are silently found in a significant proportion of unselected patients presenting with TdP. By analyzing a prospective cohort of 25 TdP subjects consecutively collected from the general population, we found the presence of anti-Ro/SSA-52kD-antibodies in over 50% of patients, in most cases without a history of AD (24). In agreement with what was observed in children with aCHB (57) and patients with CTD (66), also in this case iWB was demonstrated to be the most sensitive laboratory technique in revealing arrhythmogenic autoantibodies. Strong support for these data is provided by a very recent population study conducted in a large cohort of 7339 US Veterans, including 612 anti-Ro/SSA-positive (31). In these subjects, circulating anti-Ro/SSA-antibodies were independently associated with a ~2-times higher risk of marked QTc prolongation (>500 ms), regardless the presence or not of history of CTD. Moreover, stepwise multivariate logistic regression analysis demonstrated that anti-Ro/SSA positivity was one of the most important contributors to marked QTc prolongation, with a significant synergy with most of the concomitant traditional QT-prolonging risk factors, including antimalarials (31). In fact, accumulating evidence demonstrates that this class of drugs, commonly used for the treatment of CTD patients, can inhibit the hERG-K⁺-channel (73–75) and promote LQTS development (76). Nevertheless, by stratifying Veterans according the antimalarials use, it was demonstrated that even in the absence of these drugs subjects who were anti-Ro/SSA-positive showed a prevalence of QTc > 500 two-fold higher than in those who were anti-Ro/SSA-negative (31).

Besides the aforementioned studies, it should be noted how other authors reported that adult or pediatric anti-Ro/SSA-positive patients showed increased QTc duration and/or QTc prolongation prevalence with respect to negative controls. However, such differences approached but did not reach the statistical significance, most likely because of the undersized samples used. This is the case of four additional studies reporting slightly longer mean QTc (Gordon et al., p = 0.06; Motta et al., p = 0.06) (77, 78) or higher proportion of QTc prolongation (Nomura et al., p = 0.08; Bourré-Tessier et al., wide 95%CI) (79, 80) in the presence of circulating anti-Ro/SSA-antibodies.

While this large body of data provides robust evidence for a clinically significant association between anti-Ro/SSA-antibodies and LQTS risk, some studies involving children (81, 82) or adults (83–87) reported apparently conflicting results. Several factors may account for these discrepancies, also possibly contributing to the significant variability in anti-Ro/SSA-associated QTc prolongation frequencies even reported by positive association studies (~10-60%) (25, 66). Firstly, given that the QT-prolonging effects seems to be specifically due to the anti-Ro/SSA-52kD subtype, and in a concentration-dependent manner (23, 24, 27, 66, 69, 70), it is likely that patients in these cohorts did not present circulating levels of this autoantibody sufficient to produce measurable electrocardiographic changes. Indeed, among different CTDs, a wide variability exists in terms of anti-Ro/SSA-52kD concentrations (for example, in systemic sclerosis patients the antibody level is typically low) (85, 88, 89), and in most of the negative association studies specific subtype assessment was not executed. In addition, most of these studies were retrospective and utilized different cutoffs to define QTc prolongation, these factors also potentially contributing to inconsistencies. This is the case, for example, of the study by Teixeira et al. (83) in which the QTc was considered as prolonged when >500 ms. As a result, only 10 out of 317 SLE patients showed QTc prolongation, a sample size that is underpowered for any statistical comparison between anti-Ro/SSA-positive (4/111, 3.6%) and -negative subjects (83). Data from the recent population study on US Veterans provide new important details, which provide support to the above considerations (31). In fact, in this large cohort, where only the qualitative data of anti-Ro/SSA-positivity was considered (no information on antibody subtypes and related concentrations available) the overall prevalence of QTc prolongation > 470 ms (males)/480 ms (females) in anti-Ro/SSA-positive subjects was 10% (vs. 6.2% in anti-Ro/SSA-negative, p < 0.001) (31), a percentage underestimated since several individuals without/with low levels of anti-Ro/SSA-52kD subtype were certainly present among those labeled as anti-Ro/SSA-positive. Notably, 3.1% of the subjects with circulating anti-Ro/SSA-antibodies (vs. 1.1% in anti-Ro/SSA-negative) showed QTc prolongation > 500 ms, proportions in part similar to those found by Teixeira et al., (83) but in this case very different from a statistical point of view (p < 0.001) due to the adequate power of the sample size (31).

Finally, as discussed in more details in the following section “Experimental Data,” anti-Ro/SSA-antibodies can concomitantly inhibit multiple cardiac ion channels, resulting in conflicting effects on APD, thereby on QT interval duration on the surface ECG (21, 90). Such a multifaceted impact on cardiomyocyte electrophysiology, along with the inherent (genetic and acquired) variability in cardiac ion channels reserves among different individuals (91, 92), may also significantly contribute to the reported discrepancies among clinical studies (21, 90).

Experimental Data

Accumulating data from experimental studies based on in-vitro, ex-vivo, and in-vivo models (Table 2) (23, 24, 26, 27, 33) demonstrated that the QT-prolonging effect of anti-Ro/SSA-antibodies, specifically the anti-Ro/SSA-52kD subtype, is due to a specific cross-reaction with the cardiac hERG-K⁺ channel leading to an inhibition of the related current, I_Kr (21). The direct electrophysiological nature of such an effect can well explain why circulating anti-Ro/SSA-antibodies are per se associated with an increased risk of QTc prolongation/TdP in the clinical setting, regardless of the presence or not of an overt AD (24, 31).

TABLE 2

Table 2. Basic mechanisms of anti-Ro/SSA-associated LQTS: data from experimental studies.

Specifically, our group demonstrated that incubation of human embryonic kidney-293 cells stably expressing the hERG-K⁺-channel (HEK293-hERG) or guinea-pig ventricular myocytes with serum, purified IgGs, or affinity-purified anti-Ro/SSA-52kD obtained from CTD patients with LQTS was associated with an acute (minutes), concentration-dependent and reversible I_Kr inhibition (23). Moreover, the development of high levels of circulating anti-Ro/SSA-52kD antibodies in guinea-pigs immunized with the Ro52 antigen was associated with an evident prolongation of the APD measured in ventricular myocytes, as well as of the QTc measured at the surface ECG (23). Furthermore, by combining WB and ELISA experiments, we also provided evidence that anti-Ro/SSA-antibodies can directly cross-react with the hERG-K⁺-channel, specifically with the S5-S6 segments of the extracellular loop of the pore region where a significant sequence homology with the Ro52 antigen was demonstrated (23). Consistently, the immunization of guinea-pigs with a 31-amino acid peptide corresponding to this region of the hERG-K⁺-channel resulted in high levels antibodies able to block I_Kr, prolong APD and QTc, in the absence of any structural change at the pathology examination of the myocardium (26). In addition, a recent Canadian study provided further mechanistic insights into anti-Ro/SSA-associated QTc prolongation, explaining its long-lasting persistence as observed in the clinical setting (27). In fact, these authors demonstrated that prolonged incubation of HEK293-hERG cells with anti-Ro/SSA-52kD-positive sera from patients with rheumatic diseases significantly decreased I_Kr compared to cells treated with autoantibody-negative patients' sera (27). Moreover, they showed that anti-Ro/SSA-52kD antibodies chronically facilitated hERG endocytic degradation by targeting the extracellular S5-pore linker region of the channel, and that these changes were associated with persistent I_Kr reduction and APD prolongation in neonatal rat ventricular myocytes (27).

The same mechanisms are implicated in anti-Ro/SSA-positive subjects who develop TdP, despite the absence of a manifest AD (Table 2). The first evidence was provided by Nakamura et al. (33) who demonstrated that serum and purified IgGs from an otherwise healthy anti-Ro/SSA-positive woman presenting with marked QTc prolongation and recurring TdP, cross-reacted with the hERG-K⁺-channel and chronically blocked I_Kr in HEK293-hERG cells. Our group confirmed and refined these findings in a prospective cohort of 25 consecutive TdP patients, including 15 (60%) with circulating anti-Ro/SSA-52kD antibodies, in most cases (13/15, 87%) without a history of AD (24). Again, sera and IgGs from anti-Ro/SSA-52kD-positive subjects significantly reduced I_Kr in HEK293-hERG cells, but also in guinea-pig ventricular myocytes, and recognized the hERG-K⁺-channel by specifically interacting with the S5-S6 segment of the extracellular loop of the pore-forming region (24).

Altogether, these data robustly support the hypothesis that a direct hERG-K⁺-channel blockade is the molecular mechanism underlying QTc prolongation and TdP observed in anti-Ro/SSA-positive subjects. However, it should be noted that anti-Ro/SSA-antibodies can also cross-react with and block cardiac Ca⁺⁺-channels (48, 50–52, 54), responsible for opposite effects on APD. This view is supported by a mathematical modeling study which demonstrated how a simultaneous anti-Ro/SSA-associated inhibition of I_CaL during the plateau phase partly counterbalances the APD prolonging effect due to I_Kr decrease (26). Based on this evidence, it is likely that the inherent ion channel reserve which characterize each single subject (92) may significantly influence the overall impact of anti-Ro/SSA-antibodies on the duration of the QTc on the surface ECG, thereby contributing to explain the inconsistencies among clinical studies on the association of anti-Ro/SSA-antibodies and QTc prolongation (25). However, given that I_Kr physiologically activates after the T wave peak on the ECG (6, 93), a specific evaluation of the Tp-Te might represent a more accurate method to assess in the clinical setting, the discrete impact of anti-Ro/SSA-antibodies on this current. This also in consideration of the particularly important prognostic role that Tp-Te prolongation seems to have in predicting TdP risk (4, 5). In agreement with such premises, Tufan et al. (70) demonstrated that in anti-Ro/SSA-52kD-positive CTD patients Tp-Te was significantly prolonged when compared to anti-Ro/SSA-52kD-negative patients and healthy controls, even in those in whom the whole duration of the QTc was normal.

Conclusions

Mounting evidence from clinical and experimental studies indicates that anti-Ro/SSA-antibodies can markedly affect the ventricular repolarization via a direct inhibitory cross-reaction with the extracellular pore region of the cardiac hERG-K⁺-channel, resulting in an increased predisposition to LQTS/TdP in anti-Ro/SSA-positive patients. Notably, recent data demonstrate that such a risk is increased independent of a history of overt AD, intriguingly suggesting that these autoantibodies may also silently contribute to a number of cases of VAs and cardiac arrest in the general population (Figure 1).

FIGURE 1

Figure 1. Anti-Ro/SSA antibodies, which can inhibit the I_Kr current by directly recognizing hERG potassium channel (brownish), are independently associated with an increased risk of marked QTc prolongation in a large cohort of Veterans (white). Abs, Antibodies; I_Kr, rapidly activating component of the delayed outward-rectifying K⁺ current; hERG-K⁺, human ether-à-go-go related gene potassium channel; APD, Action potential duration; QTc, heart rate-corrected QT-interval; OR, odds ratio; CI, confidence interval.

In fact, although anti-Ro/SSA-antibodies alone cannot usually prolong QTc in a so critical manner to induce TdP development (similarly to all the other better recognized determinants of LQTS) (91, 94), nevertheless they can reduce the ventricular repolarisation reserve (92), thereby enhancing the arrhythmic risk when other conventional QT-prolonging factors (drugs, electrolyte imbalances, genetic mutations, etc.) are concomitantly present (multi-hit theory) (Figure 2) (24, 91, 95–99).

FIGURE 2

Figure 2. Anti-Ro/SSA-antibodies and the multi-hit theory of long-QT syndrome: given that manifold often-redundant ion channel mechanisms physiologically preserve ventricular APD, hence QTc length (repolarization reserve), many QT-prolonging risk factors (“hits”) need to be concomitantly present in a single patient to induce the marked disruption of ventricular repolarization necessary to the occurrence of life-threatening arrhythmias such as TdP. In the absence of QT-prolonging factors (0), I_Kr is preserved, and APD and QTc are normal. In subjects with the sole presence of arrhythmogenic anti-Ro/SSA antibodies partially inhibiting I_Kr (+1/hit 1), APD/QTc usually slightly/moderately prolongs (or even remains in the normal range, depending on pre-existing genetically-determined repolarization reserve). In these subjects, only the concomitant presence of other genetic or acquired QT-prolonging risk factors further inhibiting I_Kr and/or other key ion currents (such as drugs, electrolyte imbalances, etc.: +2/hit 2, +3/hit 3, etc.), can induce the marked APD/QTc prolongation critically required for TdP occurrence. I_Kr, rapidly activating component of the delayed outward-rectifying K⁺ current; APD, Action potential duration; EADs, early afterdepolarizations; QTc, heart rate-corrected QT-interval; TdP, Torsades de Pointes.

Based on these considerations and in some way referring to the existing guidelines on the approach to aCHB (100), it is recommended that anti-Ro/SSA-positive subjects receive serial ECGs and specific counseling about medications and management of other risk factors that may critically enhance the risk for QT-associated malignant arrhythmias. On the other hand, patients with “idiopathic” rhythm disturbances should be considered for specific anti-Ro/SSA testing (iWB technique is recommended for detecting arrhythmogenic anti-Ro/SSA subtypes), regardless the presence or not of a manifest AD, given that the demonstration of circulating antibodies may lead to innovative therapeutic opportunities. Indeed, in agreement with current recommendations for incomplete forms of aCHB (100) (and with several case reports showing the reversing effects of immunosuppressive therapy in anti-Ro/SSA–associated atrioventricular blocks in adults) (101–104), preliminary data from anti-Ro/SSA-positive CTD patients suggest that a short course immunomodulating treatment with corticosteroids is associated with a significant QTc shortening (104, 105). Larger studies are warranted to confirm these intriguing findings. Moreover, given that anti-Ro/SSA-antibodies prolong APD/QTc by directly reacting with a specific amino acid sequence of the hERG-K⁺ channel, a peptide-based therapy serving as a decoy to prevent autoantibody-channel binding may be another innovative approach, as preliminarily supported by ex-vivo data on sera from anti-Ro/SSA-positive TdP subjects (24).

Author Contributions

PL: conception and design of the work and drafting the work. PL, FL-P, MB, and PC: final approval of the version to be published. FL-P, MB, and PC: revising the draft of the work critically for important intellectual content and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors contributed to the article and approved the submitted version.

Funding

This work was funded by: 1) Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR), Progetti di Rilevante Interesse Nazionale (PRIN), and Bando 2017, protocollo 2017XZMBYX; and 2) Biomedical Laboratory Research and Development Service of Veterans Affairs Office of Research and Development (Merit Review Grant I01 BX002137 to Dr. Boutjdir).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

We thank Dr. Andrea Francioni for his contribution to the Figure 2.

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