From Systemic Inflammation to Calcium Leak: The RyR2 Hypothesis of Reversible Myocardial Dysfunction in Andes Virus Cardiopulmonary Syndrome

Hantavirus cardiopulmonary syndrome (HCPS) caused by Andes virus is a severe zoonotic disease characterized by a paradoxical cardiac phenotype: profound myocardial dysfunction that is frequently reversible in survivors and occurs without extensive structural damage. The mechanisms linking systemic inflammation to this reversible dysfunction remain unknown. This review examines the hypothesis that inflammatory signaling converges on the cardiac ryanodine receptor (RyR2), a major intracellular Ca²⁺-release channel, through post-translational modifications, generating reversible myocardial dysfunction in HCPS. In severe disease, elevated IL-6, reactive oxygen and nitrogen species, and nitrosative stress activate pathways that in experimental models converge on RyR2 through CaMKII-dependent phosphorylation at Ser2814, oxidative modification of cysteine residues, and S-nitrosylation, each destabilizing the channel and promoting diastolic Ca²⁺ leak. The resulting increase in spontaneous Ca²⁺ release reduces SR Ca²⁺ content, impairs contractility, and predisposes to arrhythmias. This framework identifies RyR2 as a plausible mechanistic hub for the reversible cardiac phenotype. Therapeutic implications are discussed, emphasizing the timing of interventions and the potential of rycals, drugs that stabilize the closed state of RyR2 and prevent diastolic Ca²⁺ leak, as an emerging strategy. This model provides a testable hypothesis for a disease that currently lacks specific treatment.