This study shows that the NLRP3 inflammasome is up-regulated in myocardial fibroblasts post-MI, and may be a significant contributor to infarct size development during ischaemia-reperfusion.
Evidence from both experimental and clinical trials indicates that inflammatory mediators are of importance in the pathogenesis of chronic heart failure (HF) contributing to cardiac remodeling and peripheral vascular disturbances. Several studies have shown raised levels of inflammatory cytokines such as tumor necrosis factor (TNF)α, interleukin (IL)-1β and IL-6 in HF patients in plasma and circulating leukocytes, as well as in the failing myocardium itself. There is strong evidence that these mediators are involved in processes leading to cardiac remodeling such as hypertrophy, fibrosis and apoptosis. Some of these cytokines can also give useful prognostic information as reliable biomarkers in this disorder. In general, immunomodulating treatments have, with a few exceptions, been neutral or even harmful. However, the negative results of anti-TNF studies, for instance, do not necessarily argue against the ‘cytokine hypothesis’. These studies just underscore the challenges in developing treatment modalities that can modulate the cytokine network in HF patients and result in beneficial net effects. Future studies should identify the crucial actors and their mechanisms of action in the immunopathogenesis of chronic HF and, in particular, clarify the balance between adaptive and maladaptive effects of these molecules. Such studies are a prerequisite for the development of new treatment strategies that target inflammatory and immunopathogenic mechanisms in HF. In this review article, these issues are thoroughly discussed, and we also argue for the possibility of future therapeutic targets such as mediators in innate immunity, chemokines and mediators in matrix remodeling.
Sustained pressure overload leads to compensatory myocardial hypertrophy and subsequent heart failure, a leading cause of morbidity and mortality. Further unraveling of the cellular processes involved is essential for development of new treatment strategies. We have investigated the hypothesis that the transmembrane Z-disc proteoglycan syndecan-4, a co-receptor for integrins, connecting extracellular matrix proteins to the cytoskeleton, is an important signal transducer in cardiomyocytes during development of concentric myocardial hypertrophy following pressure overload. Echocardiographic, histochemical and cardiomyocyte size measurements showed that syndecan-4−/− mice did not develop concentric myocardial hypertrophy as found in wild-type mice, but rather left ventricular dilatation and dysfunction following pressure overload. Protein and gene expression analyses revealed diminished activation of the central, pro-hypertrophic calcineurin-nuclear factor of activated T-cell (NFAT) signaling pathway. Cardiomyocytes from syndecan-4−/−-NFAT-luciferase reporter mice subjected to cyclic mechanical stretch, a hypertrophic stimulus, showed minimal activation of NFAT (1.6-fold) compared to 5.8-fold increase in NFAT-luciferase control cardiomyocytes. Accordingly, overexpression of syndecan-4 or introducing a cell-permeable membrane-targeted syndecan-4 polypeptide (gain of function) activated NFATc4 in vitro. Pull-down experiments demonstrated a direct intracellular syndecan-4-calcineurin interaction. This interaction and activation of NFAT were increased by dephosphorylation of serine 179 (pS179) in syndecan-4. During pressure overload, phosphorylation of syndecan-4 was decreased, and association between syndecan-4, calcineurin and its co-activator calmodulin increased. Moreover, calcineurin dephosphorylated pS179, indicating that calcineurin regulates its own binding and activation. Finally, patients with hypertrophic myocardium due to aortic stenosis had increased syndecan-4 levels with decreased pS179 which was associated with increased NFAT activation. In conclusion, our data show that syndecan-4 is essential for compensatory hypertrophy in the pressure overloaded heart. Specifically, syndecan-4 regulates stretch-induced activation of the calcineurin-NFAT pathway in cardiomyocytes. Thus, our data suggest that manipulation of syndecan-4 may provide an option for therapeutic modulation of calcineurin-NFAT signaling.
Our aim was to establish parameters describing systolic and diastolic function in mice after myocardial infarction (MI) that distinguish MI with pulmonary congestion from MI without congestion. Echocardiography, left ventricular (LV) catheterization, and infarct size measurements were performed on days 3, 5, 7, and 14 after ligation of the left coronary artery in C57BL/6 mice. Sham-operated mice were used as controls (Sham). MI mice with lung weight normalized to tibial length >125% of the average in the corresponding Sham group were considered to have pulmonary congestion (MIchf). MI mice with a smaller increase were called MI nonfailing (MInf). An infarct >40% of total LV circumference measured in two-dimensional long axis distinguished MIchf from MInf on both an average and an individual basis. Mean maximum rate of rise of LV pressure, LV fractional shortening, and posterior wall shortening velocity were significantly lower in MIchf compared with Sham at all time points and to MInf at 7 days. The diastolic parameters mitral flow deceleration velocity, LV end-diastolic pressure, and maximum rate of decline in LV pressure (LVdP/dtmin) discriminated the MIchf groups from Sham at all time points. Mitral flow deceleration velocity and LVdP/dtmin separated MIchf from MInf at 7 days. In addition to distinguishing all the groups on an average basis, left atrial diameter distinguished all MIchf animals from Sham and MInf. In conclusion, significantly increased left atrial diameter and infarct size >40% of total LV circumference may serve as major criteria for heart failure with pulmonary congestion after MI in mice.
The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701).
Background: B-type natriuretic peptide (BNP) measurements are useful for diagnosing congestive heart failure (CHF) in patients presenting to the Emergency Department with acute dyspnoe. Whether the diagnostic accuracy of BNP is affected by the age and gender of the patients remains unknown. Aims: To evaluate the accuracy of BNP testing for diagnosing CHF in an unselected group of patients admitted to the emergency department of a Norwegian teaching hospital with a principal complaint of shortness of breath and to assess whether the diagnostic accuracy of the test differs according to age and gender. Methods: BNP levels in plasma were determined by a point-of-care device upon arrival in 155 patients presenting with acute dyspnoe. The diagnostic 'gold' standard for CHF was adjudicated by two independent cardiologists who were blinded to the BNP data. Results: By univariate logistic regression analysis, BNP was strongly related to a diagnosis of CHF. In a multivariate model BNP provided additional prognostic information to patient age and gender, radiographic evidence of pulmonary congestion and cardiomegaly, and the presence of pulmonary rales and jugular vein distention by physical examination. There was no significant interaction between age and BNP or between gender and BNP with regard to the accuracy of diagnosing CHF. The area under the receiveroperating characteristics-curve was 0.86 (95% confidence interval 0.78-0.93) in women and 0.90 (0.82-0.97) in men. The area under the curves were 0.82 (0.73-0.92) and 0.88 (0.80-0.97) for patients (both genders) aged 076 and -76 years, respectively. Conclusion: Point-of-care BNP measurement in the emergency department discriminates well between patients with dyspnoe of cardiac and non-cardiac origin regardless of age and gender.
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