Cardiac amyloidosis exhibits a distinct PAR2-linked transcriptional program

Background Cardiac amyloidosis lacks biomarkers that reflect disease-driving biological pathways rather than downstream myocardial stress. Proteomic studies have identified a conserved amyloid plaque–associated protein signature, implicating innate immune and proteostasis mechanisms, but its transcriptional regulation in human myocardium remains unclear. Methods Myocardial gene expression was analyzed in endomyocardial biopsies from patients with cardiac amyloidosis (ATTR and AL, n = 14) and dilated cardiomyopathy (DCM) controls (n = 20). Differential expression and gene–gene correlations of innate immune, chaperone, and complement pathways were assessed and related to imaging markers of disease severity. Findings were complemented by analyses in young and aged wild-type and PAR2 knockout mice, and by PAR2 and/or TLR4 induction in HepG2 hepatocytes. Results Compared with DCM, cardiac amyloidosis showed coordinated upregulation of TLR4 pathway components and amyloid-associated genes, including MYD88 (Δ = +3.00, p < 0.001), TLR4 (Δ = +2.97, p < 0.001), TRIF (Δ = +3.47, p < 0.001), PAR2/F2RL1 (Δ = +2.75, p < 0.001), C3 (Δ = +2.70, p < 0.001), CLU (Δ = +2.24, p < 0.001), and VTN (Δ = +1.69, p < 0.001). In cardiac amyloidosis, PAR2 was strongly correlated with TLR4 (r = 0.70, p = 0.006), C3 (r = 0.80, p < 0.001), CLU (r = 0.77, p = 0.001), MYD88 (r = 0.73, p = 0.003), and VTN (r = 0.72, p = 0.004). In contrast, PAR2–TLR4 correlation was weak and non-significant in DCM (r = 0.36, p = 0.12). Myocardial PAR2 expression correlated with markers of amyloid burden, including apical sparing (r = 0.57, p < 0.001), Perugini score (r = 0.64, p = 0.035), and left ventricular mass (r = 0.58, p = 0.031). In aged PAR2 knockout mice, expression of amyloid-associated and innate immune genes was broadly reduced in liver and heart, including APOE (Δ = −0.480), APOA4 (Δ = −0.415), CLU (Δ = −0.518), VTN (Δ = −0.388), SAP (Δ = −0.395), TLR4 (Δ = −0.392), MYD88 (Δ = −0.502), TRIF (Δ = −0.547), and IL6 (Δ = −0.519). In HepG2 hepatocytes, LPS induced coordinated upregulation of amyloid-associated genes, which was markedly attenuated by PAR2 antagonism. Conclusions Cardiac amyloidosis is associated with a PAR2–TLR4–linked myocardial and hepatic transcriptional signature. Myocardial PAR2 expression correlates with imaging-defined amyloid burden, supporting its potential utility as a pathway-linked tissue biomarker.