In patients with HF, collagen metabolism is altered by MMPs/TIMPs and cytokine gene expression in different tissue, resulting in the upregulation of MMP-2, MMP-9, TIMP-1, TIMP-2, TIMP-3 and TIMP-4 genes.28,29 Thus, matrix remodeling and collagen types I and III imbalance are resulted in an increased degree of fibrosis in HF.30 The possible(s) molecular mechanism is enhanced IL-6 and TNF-α could up-regulate MMPs expression through activating of cyclooxygenase-2, PGE2 and microsomal prostaglandin synthase 1, culminating to JAK-STAT and MAPK (erk1/2)-signaling pathways activation.30-32. This evidence concerns the gene TIMP4 and hydrops fetalis.