Long COVID-19 (LC19) has left millions of survivors grappling with
cardiovascular complications, particularly myocarditis and thrombosis,
which significantly elevate mortality risk through mechanisms of
sustained inflammation and oxidative stress (1, 2) .
Corticosteroids have become a principal therapeutic approach, with
meta-analyses validating their effectiveness in decreasing mortality in
critically ill patients (3, 4) . However, their long-term
administration often results in significant side effects, including
metabolic disorders and sleep disruption, which can limit treatment
adherence and effectiveness.
In this article, we propose a novel chronotherapeutic solution: morning
administration of corticosteroids, aligned with natural cortisol peaks(5) , complemented by evening melatonin doses (6) . This
strategic timing could enhance therapeutic outcomes through two
mechanisms: First, optimizing the anti-inflammatory effects of
corticosteroids through circadian alignment, and second, leveraging
melatonin’s established antioxidant and cardioprotective properties
while mitigating corticosteroid-induced sleep disturbances.
Meta-analyses have established corticosteroids as a cornerstone
treatment for COVID-19, demonstrating significant reductions in
mortality rates among critically ill patients (4) . Their
therapeutic action centers on suppressing the excessive inflammatory
response that characterizes severe disease progression (3) .
Regarding LC19’s cardiovascular manifestations, corticosteroids directly
address myocarditis through immunosuppression and reduce thrombotic risk
by dampening systemic inflammation. Despite these benefits, prolonged
corticosteroid administration presents substantial challenges. Sleep
disruption occurs through interference with the
hypothalamic-pituitary-adrenal axis, while metabolic effects manifest as
weight gain and glucose dysregulation (5) . Beyond diminishing
quality of life, corticosteroid-induced circadian and metabolic
disturbances can heighten cardiovascular risk (5) .
Melatonin’s established safety profile and diverse therapeutic
properties position it as an ideal complement to corticosteroid therapy.
Melatonin offers cardioprotection via multiple pathways distinct from
its chronobiological benefits. It enhances mitochondrial bioenergetics,
promotes autophagy of dysfunctional cardiac cells, and reduces
apoptosis, thereby preserving cardiac tissue integrity (7) .
Additionally, melatonin’s inhibition of NLRP3 and activation of NRF2
pathways provides anti-inflammatory and antioxidant effects that could
potentially allow for reduced corticosteroid dosing (7) . In the
context of thrombotic complications, melatonin’s antithrombotic
properties offer further benefits. It improves endothelial function,
reduces platelet aggregation, and enhances fibrinolytic capacity through
downregulation of plasminogen activator inhibitor-1 (8, 9) .
These effects directly address the prothrombotic environment
characteristic of LC19, while complementing the anti-inflammatory action
of corticosteroids.
The optimal timing of corticosteroid and melatonin administration aligns
with natural circadian rhythms to maximize therapeutic benefits. Morning
corticosteroid dosing coincides with peak endogenous cortisol
production, enhancing anti-inflammatory effects while minimizing
circadian disruption (5) . Evening melatonin restores cortisol
secretion patterns altered by LC19 and corticosteroid therapy. With
aging and in post-infectious states, melatonin production typically
declines while cortisol peaks shift earlier, disrupting the natural
endocrine balance (10) . Exogenous melatonin administration has
demonstrated the ability to rectify early-onset cortisol production,
potentially optimizing the therapeutic window for corticosteroid
treatment. This timing-based approach may enhance treatment efficacy
while reducing the required corticosteroid dosage, thereby minimizing
side effects.
The translation of this promising chronotherapeutic approach into
clinical practice demands innovative and immediate action from the
global research community. We propose establishing a Global LC19
Chronotherapy Consortium (GLCC) to unite experts in chronobiology,
cardiovascular medicine, clinical pharmacology, machine learning, and
big data science. The consortium would leverage advanced monitoring
systems and telemedicine for comprehensive clinical data collection.
This digital infrastructure, combined with patient-centered trial
designs and input from patient advocacy groups, would not only support
rigorous clinical investigation but also facilitate seamless
implementation across diverse healthcare settings. While our theoretical
framework is promising, we acknowledge that clinical translation may
yield varying results across different patient populations and
healthcare contexts. The accessibility and safety profiles of both
agents present a unique opportunity to address health equity concerns,
particularly in resource-limited regions. We urgently call upon research
institutions, funding bodies, and healthcare systems worldwide to
embrace this initiative through coordinated, technology-enabled,
multi-center trials that can definitively establish the role of
chronotherapeutic optimization in LC19 treatment. However, these
investigations must maintain rigorous methodological standards and
critical evaluation of outcomes, as the complexity of chronobiological
interventions may present unexpected challenges. The time for action is
now - millions of patients await evidence-based solutions, and we stand
at a crucial intersection where theoretical understanding, technological
capability, and global health needs converge to potentially transform
the landscape of LC19 cardiovascular care.