Heart Failure Relapses in Response to Acute Stresses - Role of Immunological and Inflammatory Pathways.

Cardiovascular diseases continue to be the most imminent health care problems in the western world, accounting for numerous deaths per year. Heart failure (HF), namely the reduction of left ventricular function, is one of the major cardiovascular disease entities. It is chronically progressing with relapsing acute decompensations and an overall grave prognosis that is little different if not worse than most malignant diseases. Interestingly acute metabolically and/or immunologically challenging events like infections or major surgical procedures will cause relapses in the course of preexisting chronic heart failure, decrease the patients wellbeing and worsen myocardial function. HF itself and or its progression has been demonstrated to be driven at least in part by inflammatory pathways that are similarly turned on by infectious or non-infectious stress responses. These thus add to HF progression or relapse. TNF-α plasma levels are associated with disease severity and progression in HF. In addition, several cytokines (e.g., IL-1ß, IL-6) are involved in deteriorating left ventricular function. Those observations are based on clinical studies using inhibitors of cytokines or their receptors or they stem from animal studies examining the effect of cytokine mediated inflammation on myocardial remodeling in models of heart failure. This short review summarizes the known underlying immunological processes that are shared by and drive all: chronic heart failure, select infectious diseases, and inflammatory stress responses. In conclusion the text provides a brief summary of the current development in immunomodulatory therapies for HF and their overlap with treatments of other disease entities.

[Pneumonia, endocarditis of two valves and pulmonary artery embolism in a 26-year-old male patient]. / Pneumonie, Zweiklappenendokarditis und Lungenarterienembolie bei einem 26-jährigen Patienten.

A 26-year-old male patient presented with left-sided pneumonia, endocarditis of the tricuspid and pulmonary valves and a pulmonary artery embolism. In 2004 a Ross operation was performed because of congenital aortic valve stenosis. There was an elevation of the antibody titer for Coxiella burnetii, the pathogen of Q fever. Under antibiotic treatment with levofloxacin and doxycycline there was an improvement of the symptoms and a normalization of the inflammation parameters. The treatment of the endocarditis was successful.

Fibulin-6 regulates pro-fibrotic TGF-ß responses in neonatal mouse ventricular cardiac fibroblasts.

Fibulin-6, an essential component of extracellular matrix determines the architecture of cellular junctions in tissues undergoing strain. Increased expression and deposition of fibulin-6 facilitates fibroblast migration in response to TGF-ß, following myocardial infarction in mouse heart. The underlying mechanism still remains elusive. In conjunction with our previous study, we have now demonstrated that in fibulin-6 knockdown (KD) fibroblasts, not only TGF-ß dependent migration, but also stress fiber formation, cellular networking and subsequently fibroblast wound contraction is almost abrogated. SMAD dependent TGF-ß pathway shows ~75% decreased translocation of R-SMAD and co-SMAD into the nucleus upon fibulin-6 KD. Consequently, SMAD dependent pro-fibrotic gene expression is considerably down regulated to basal levels both in mRNA and protein. Also, investigating the non-SMAD pathways we observed a constitutive increase in pERK-levels in fibulin-6 KD fibroblast compared to control, but no change was seen in pAKT. Immunoprecipitation studies revealed 60% reduced interaction of TGF-ß receptor II and I (TGFRII and I) accompanied by diminished phosphorylation of TGFRI at serin165 in fibulin-6 KD cells. In conclusion, fibulin-6 plays an important role in regulating TGF-ß mediated responses, by modulating TGF-ß receptor dimerization and activation to further trigger downstream pathways.

Expression of fibulin-6 in failing hearts and its role for cardiac fibroblast migration.

AIMS: The cardiac extracellular matrix (ECM) undergoes a dynamic transition following myocardial infarction. Fibulin-6 is expressed in cell junctions particularly in tissues subjected to significant mechanical stress. Fibulin-6 deficiency results in defective cell migration in nematodes and early embryonic lethality in mice. The role of fibulin-6 in healthy and failing myocardium is unknown. We have examined the expression and distribution pattern of fibulin-6 during myocardial remodelling (MR) and detailed its effect on the migratory function of cardiac fibroblasts (CFs) in response to TGF-ß1. METHODS AND RESULTS: In healthy murine myocardium, fibulin-6 expression is largely confined to larger coronary arteries. It is induced during the early and the late phase of remodelling after infarction in murine hearts predominantly in the scar-muscle junction. Similar results are obtained in human ischaemic cardiomyopathy. Fibulin-6 is mostly expressed in close vicinity to vimentin-positive cells and is also abundantly expressed in vitro in cultured neonatal CF. TGF-ß1 does not induce smooth muscle actin in fibroblasts deficient of fibulin-6, which also compromised their migration. Cells that had migrated expressed more fibulin-6 compared with stationary cells. Plated on fibulin-6-depleted matrix, stress fibre induction in fibroblast in response to TGF-ß1 was impaired. In ex vivo explant cultures from post-infarct myocardium, the number of emigrating fibroblasts was also significantly reduced by fibulin-6 siRNA knockdown. CONCLUSION: Fibulin-6, a fibroblast-released ECM protein, may play an important role during MR by imparting an effect on CF migration in close and complementary interplay with TGF-ß1 signalling.