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.