4. Discussion
The study provides evidence that glucocorticoids are associated with a
reduction of myocardial injury in patients admitted with CAP.
Furthermore, corticosteroids were associated with a lower incidence of
MACE in a long-term follow-up. The effect of corticosteroids seems to be
mediated by an antioxidant mechanism related to Nox2 down-regulation.
Previous studies showed that myocardial injury, as assessed by cardiac
troponins elevation, is commonly detected in pneumonia. In a cohort of
hospitalized CAP, we previously showed that elevated levels of hs-cTnT
(> 0.014 µg/L; i.e. over the 99thpercentile) were found in more than 50% of patients and associated to
in hospital MI in about 10% of patients.5 The
increase of hs-cTnT was mostly detected within 24 -72 h from hospital
admission, indicating that myocardial damage, as well as the risk of MI,
were maximally evident in the first days of hospitalization.
In a cohort of 295 CAP patients in the Netherlands, Vestjens SMT al
confirmed that hs-cTnT elevation is common at hospital admission and
showed that hs-cTnT elevation is an independent predictor of short- and
long- term mortality.22 Recently, in a cohort of 730
CAP patients followed-up for one year, Menéndez R found that hs-cTnT
elevation at admission independently predicted early but not late
cardiovascular events.23 In the present study, we
extended these previous reports, underlying the importance of measuring
hs-cTnT to identify patients at risk for cardiovascular events. In our
study, hs-cTnT were evaluated not only at admission, but also every 12
hours up to 72 hours. Thus, we showed that maximum levels of in hospital
hs-cTnT (i.e. at 24-72 hours) were a strong predictor of MACE in a dose-
dependent fashion, during long-term follow-up.
We recently reported a potential role for systemic corticosteroids in
reducing MI risk in patients with CAP, indicating that this drug
category could encompass a vascular protection effect in this
setting.11 However, no data exist about the potential
effect corticosteroid on in hospital myocardial injury or long-term
cardiovascular events. In the present study we found that systemic
corticosteroids reduced troponin increase in patients with troponin
elevation during hospitalization, while no changes were detected in
patients with normal troponin. Moreover, in patients disclosing troponin
increase, in-hospital corticosteroid use was independently associated
with a reduction in MACE incidence at a long-term follow-up.
Interestingly, no difference in MACE incidence was found in patients who
did not disclose troponin increase during hospitalization.
Troponin elevation has been associated to Nox2 up-regulation in patients
with CAP suggesting that Nox2- dependent oxidative stress is implicated
in myocardial injury.24 Nox2 is among the most
important enzymes generating reactive oxidant species (ROS) in the
vasculature. ROS production has been proved to have several detrimental
effects on the myocardium, such as apoptotic cell death, hypertrophy and
dysfunction.25 Numerous studies indicated that Nox2
localizes in cardiomyocytes where it could play an important role in
redox balance,26,27 suggesting that enhanced
Nox2-derived oxidative stress may be implicated in myocardial injury.
Overactivation of Nox2 in CAP patients may be explained by previous
report indicating that single stranded RNA viruses irrespective of their
classification including influenza A virus and DNA viruses infect cells
via Toll-like 7-mediated Nox2 activation and that the virus
pathogenicity is abolished in Nox2 knock-out cells.28
Then, we investigated if corticosteroid use could reduce Nox2 activation
in this setting. At admission, patients disclosed elevated
concentrations of sNox2-dp, a marker of Nox2 activation, that correlated
to hs-cTnT levels and were reduced at hospital dismission. Patients
treated with systemic corticosteroid showed a stronger reduction in
serum sNox2-dp than not-treated ones; such a phenomenon was particularly
evident in patients disclosing troponin elevation. To explore the
biological plausibility of this finding, we performed in vitro
experiments to assess if corticosteroids modulate Nox2 activation and
ROS production. These experiments showed that corticosteroids, at
concentrations detected in human blood in after administration,
decreased Nox2 activation and H2O2production in LPS stimulated cells, through a reduction in AKT and
p47phox phosphorylation.
The present study has limitation and implication. The study supports and
extends previous reports indicating that patients with troponin
elevation are at higher risk of long-term MACE. Patients with troponin
elevation may benefit from corticosteroid treatment to improve vascular
outcomes. However, the results of our study could be biased by its
retrospective nature and by the fact that patients were not randomized
to corticosteroid treatment. Corticosteroids were administered at the
discretion of the managing physician for perceived need. However,
corticosteroid-treated patients were older and with more commorbidities
like COPD; thus this fact should reinforce the results of the present
report. Even if the herewith reported antioxidant effect and previous
reports showing glucocorticoids’ antiplatelet
effects18 could explain the cardiovascular protection,
the reasons for MACE reduction during the long-term follow-up need to be
further investigated.
The beneficial effect of corticosteroid treatment in term of myocardial
injury reduction and MACE risk were present only in patients disclosing
hs-cTnT elevation. This finding could have important implications as it
suggests the usefulness of glucocorticoids only in a subset of CAP
patients. This may be in accordance with previous reports showing that
corticosteroids reduce morbidity and mortality only in case of severe
CAP.29 Thus, we suggest the need of planning RCT to
assess if CAP patients with elevated troponin could have beneficial
effect by corticosteroid treatment in terms of myocardial injury
reduction and ultimately MACE risk reduction.
Nox2 overactivation in CAP patients might have important implications
not only in CAP patients but also in other infections mediated by RNA
viruses such as COVID-19. Thus, COVID-19 patients often present elevated
troponin levels, which are associated with poor
outcomes.30 Due to the role of Nox2 in the
pathogenesis of RNA viruses, our findings suggest to evaluate if Nox2
activation is implicated in the pathogenicity of COVID-19; in fact, Nox2
oxidase activation down-regulates antibody production, that is required
for virus clearance.28
In conclusion, in patients with CAP the increase of troponin is a marker
of poor outcomes in terms of MACE. In patients with troponin elevation
corticosteroid treatment may protect against myocardial damage and poor
cardiovascular outcomes.
Funding: This work was supported by a grant from Sapienza
University of Rome (grant. n. RM118164366B89BD).