These findings indicate that high plasma BNP and IL-6 levels three months after optimized treatment are independent risk factors for mortality in patients with CHF, suggesting that sustained high plasma levels of BNP and IL-6 after additional standard treatment were independent risk factors for mortality in patients with CHF despite improvements in LVEF and symptoms.

These findings indicate that four months of treatment with spironolactone improved the left ventricular volume and mass, as well as decreased plasma level of BNP, a biochemical marker of prognosis and/or ventricular hypertrophy, suggesting that endogenous aldosterone has an important role in the process of left ventricular remodeling in nonischemic patients with CHF.

Background— Angiotensin (Ang) II, which plays a crucial role in the cardiac remodeling process, is generated via angiotensin-converting enzyme (ACE); however, an alternative generation pathway, chymase, which is stored in the mast cells, also exists in the heart. Cardiac chymase is insensitive to ACE inhibitors (ACEIs), and heart chymase promotes interstitial fibrosis by affecting collagen metabolism via transforming growth factor-β in vitro. Therefore, selective chymase blockade seems to be an important strategy in the prevention of cardiac remodeling Methods and Results— We evaluated the effects of a specific chymase inhibitor, SUNC8257 (Chy I; 10 mg/kg twice a day; n=7), on changes in cardiac structures, Ang II levels, and gene expressions, which are characterized as molecular markers for fibrosis, in dogs with tachycardia induced heart failure (HF). In HF, the number of chymase enzyme–positive mast cells increased in the left ventricle (LV) compared with the normal group; however, Chy I significantly decreased the mast cell density and cardiac Ang II levels. Despite no significant differences in LV systolic function compared with the vehicle group, Chy I decreased LV end-diastolic pressure and shortened the prolongation of τ. Chy I suppressed collagen-type I and III and transforming growth factor-β mRNA levels and decreased fibrosis in the LV compared with the vehicle. Conclusion— The chymase pathway may be critical for cardiac diastolic dysfunction accompanied with fibrosis. Chronic chymase inhibition may therefore become an important strategy in the prevention of cardiac remodeling in HF.

This study shows that circulating TNF-alpha/sTNFR1 and IL-6/sIL-6R levels are significantly increased in NASH patients as compared with simple steatosis patients and healthy volunteers, and that these increased levels may be implicated in the pathogenesis of NASH.

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These findings suggest that 14 weeks of treatment with an Ang II type 1 receptor antagonist (candesartan cilexetil) decreased plasma levels of the immune markers such as TNFalpha, IL-6, sICAM-1 and sVCAM-1 and that it improved the biological compensatory action of endogenous cardiac natriuretic peptides in patients with mild to moderate CHF.

The pathogenesis of primary biliary cirrhosis (PBC) remains enigmatic. In order to address this issue, we analyzed by laser capture microdissection and real-time reverse transcription-polymerase chain reaction the site-specific expression of messenger RNA (mRNA) for cytokines (interferon (IFN)-a, -b, -c, interleukin (IL)-1b, -4, -6, -10, -12p40, -18, tumor necrosis factor-a) and toll-like receptors (TLRs) (TLR-2, -3, -4, -7, -9) in portal tract and liver parenchyma from patients with early-stage PBC. Expression of IFN-a, -b and TLR-3 proteins was also studied by immunohistochemistry. Autoimmune hepatitis (AIH) and chronic hepatitis C (CHC) served as disease controls. The expression levels of type I IFN (IFN-a, -b) and TLR-3 mRNAs, which are known to induce type I IFN, were significantly higher in portal tract and liver parenchyma as compared to AIH and CHC. A strong positive correlation between the mRNA levels of type I IFN and TLR-3 was also seen in both areas. Immunohistologically, IFN-a is present in the mononuclear cells in portal tract and sinusoidal cells. Macrophages in portal tract and hepatocytes expressed IFN-b and TLR-3. Furthermore, the level of IFN-a mRNA in the portal tract was positively correlated with serum alkaline phosphatase. In conclusion, these data indicate that TLR-3 and type I IFN signaling pathways are active in both the portal tract and liver parenchyma of early-stage PBC, and form the basis for our hypothesis that these signaling pathways are involved in the pathophysiology of PBC. Laboratory Investigation (2005) 85, 908-920.