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. 2021 Mar 16;184(8):2167–2182.e22. doi: 10.1016/j.cell.2021.03.026

Figure 6.

Figure 6

INCB054329 prevents cardiac dysfunction in a mouse lipopolysaccharide-induced cytokine storm model and in response to COVID-19 patient serum

(A) Schematic for (B)–(D).

(B) INCB054329 blocks cytokine induction 6 h after lipopolysaccharide injection. n = 5–6 mice.

(C) INCB054329 blocks induction of Lgals3bp 6 h after lipopolysaccharide injection. n = 5–6 mice.

(D) Kaplan-Meier curve of survival after lipopolysaccharide injection. n = 12 control and 11 INCB054329 treatment (67 mg/kg).

(E) Schematic for (F).

(F) INCB054329 prevents the reduction in ejection fraction 6 h after lipopolysaccharide injection. n = 3–4 mice at 0 and 1.5 h, and n = 8 at 6 h.

(G) Schematic for (H)–(K).

(H) IFN-γ was not higher in patients with elevated cardiac troponin I (CTNI >0.5 ng/mL). n = 27.

(I) IFN-γ was higher in patients with elevated brain natriuretic peptide (BNP >0.3 ng/mL). n = 27.

(J) Serum from COVID-19 patients with elevated brain natriuretic peptide induces diastolic dysfunction. Orange highlights human cardiac organoids with elevated force of contraction. Blue highlights dysfunctional human cardiac organoids.

(K) Diastolic dysfunction induced by COVID-19 patient 6 serum is prevented by 1 μM INCB054329. n = 4–9 human cardiac organoids from 1 experiment.

(L) LGALS3BP is induced by CS and repressed by bromodomain and extraterminal protein inhibition in human cardiac organoids. n = 3 each (2 human cardiac organoids pooled per n).

LPS, lipopolysaccharide; CS, cardiac cytokine storm. Data presented as mean ± SEM. HES3 line, human pluripotent stem cell-derived cardiac cells; RM3.5 line, endothelial cells. p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, and ∗∗∗∗p < 0.0001, using one-way ANOVA with Tukey’s multiple comparisons test (B and C), with Dunnett’s multiple comparisons test compared to CTRL serum (J and K) or CS (L), or using two-way ANOVA with Sidak’s multiple comparisons test (F) or Mann-Whitney (I). p value calculated using Gehan-Breslow-Wilcoxon test (D). Additional patient data are provided in Tables S2A and S2B.