A combinatorial attack strategy uncovers a molecular rationale for treating inflammatory cardiomyopathy

Here we show how the cardiac transcriptome evolves during murine myocarditis revealing early and persistent activation of cytokine and chemokine-signalling pathways together with innate immune, antigen-presentation, complement and cell-adhesion pathway activation. We identified a 50-gene subnetwork based on expression importance and quantified network tolerance to combinatorial node removal to determine target-specific therapeutic potential. Combinatorial attack of Traf2, Nfkb1, Rac1 and Vav1 causes 80% subnetwork disconnection. NFKB1 and RAC1 are targeted by prednisolone and azathioprine, creating 56% network disconnection, establishing a molecular rationale for immunosuppressive therapy. Additional combinatorial attack of BTK and PIK3CD with approved therapeutics causes 72% network disconnection, suggesting that they could be re-purposed to treat inflammatory cardiomyopathy. We propose that the combinatorial attack strategy developed here could be applied to other immune-mediated diseases. Overall design: Analyzing evolution of cardiac transcriptome during development of autoimmune myocarditis