Cytokinic storm and heart failure
The most severe stages of COVID-19 infection are characterized by a
hyperinflammatory state caused by a cytokinic storm. The term indicates
the role of the immune system in producing an uncontrolled and
generalized inflammatory response (17). This uncontrolled inflammatory
response causes severe lung injury and cardiac damage (18) (19).
The data clearly indicate that the uncontrolled and sudden release by
immuno effector cells of large amounts of pro-inflammatory cytokines
(IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33, TNF-α, TGF-β) (20) and
chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3, CCL5) causes the aberrant
systemic inflammatory response causing multi-organ dysfunction
(21)(22)(23)(24) and cardiac damage. Pro-inflammatory cytokines are
particularly responsible for cardiac damage. Several studies show that
TNF-α plays a central role in myocardial contractility depression
through various time-dependent mechanisms. The cardiodepressant effect
of TNF-α is the consequence of a signaling dependent on nitric oxide
synthase (NOS), a high concentration of Nitric Oxide (NO) in fact leads
to (25) to an inotropic negative effect (26) and to deep systolic and
diastolic dysfunction (27). TNF-a also induces apoptosis in cardiac
myocytes (28), which contributes to thinning of the left ventricular
wall (29)(30). At the molecular level, sustained overexpression of TNF-a
activates both the intrinsic and extrinsic apoptotic pathways and leads
to progressive loss of antiapoptotic proteins (31).
IL-6 is a powerful mediator of myocardial depression, which in turn
enhances the cardiodepressant effects of TNF-a and IL-1 (32). The
inotropic negative effect of IL-6 is the result of JAK2/STAT3mediated
activation of iNOS (33). IL-1 also produces prolonged decrease in
myocardial contractility (34) Finally IL-18 stimulates proinflammatory
cytokines with known cardiodepressant effects, i.e., TNF-a, IL-1a,
IL-1b, IL-6 (35)(36), and also IL-18 has been shown to induce NO
synthesis (36), which mediates myocardial dysfunction. Finally through
different mechanisms of action the proinflammatory cytokines described
above mediate contractile dysfunction and myocytic cardiac apoptosis
with cardiac damage.