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Interleukin-16 promotes cardiac fibrosis and myocardial stiffening in heart failure with preserved ejection fraction.

Tamaki S, Mano T, Sakata Y, Ohtani T, Takeda Y, Kamimura D, Omori Y, Tsukamoto Y, Ikeya Y, Kawai M, Kumanogoh A, Hagihara K, Ishii R, Higashimori M, Kaneko M, Hasuwa H, Miwa T, Yamamoto K, Komuro I - PLoS ONE (2013)

Bottom Line: Enhanced cardiac expression of IL-16 in transgenic mice induced cardiac fibrosis and LV myocardial stiffening accompanied by increased macrophage infiltration.Treatment with anti-IL-16 neutralizing antibody ameliorated cardiac fibrosis in the mouse model of angiotensin II-induced hypertension.Our data indicate that IL-16 is a mediator of LV myocardial fibrosis and stiffening in HFpEF, and that the blockade of IL-16 could be a possible therapeutic option for HFpEF.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.

ABSTRACT

Background: Chronic heart failure (CHF) with preserved left ventricular (LV) ejection fraction (HFpEF) is observed in half of all patients with CHF and carries the same poor prognosis as CHF with reduced LV ejection fraction (HFrEF). In contrast to HFrEF, there is no established therapy for HFpEF. Chronic inflammation contributes to cardiac fibrosis, a crucial factor in HFpEF; however, inflammatory mechanisms and mediators involved in the development of HFpEF remain unclear. Therefore, we sought to identify novel inflammatory mediators involved in this process.

Methods and results: An analysis by multiplex-bead array assay revealed that serum interleukin-16 (IL-16) levels were specifically elevated in patients with HFpEF compared with HFrEF and controls. This was confirmed by enzyme-linked immunosorbent assay in HFpEF patients and controls, and serum IL-16 levels showed a significant association with indices of LV diastolic dysfunction. Serum IL-16 levels were also elevated in a rat model of HFpEF and positively correlated with LV end-diastolic pressure, lung weight and LV myocardial stiffness constant. The cardiac expression of IL-16 was upregulated in the HFpEF rat model. Enhanced cardiac expression of IL-16 in transgenic mice induced cardiac fibrosis and LV myocardial stiffening accompanied by increased macrophage infiltration. Treatment with anti-IL-16 neutralizing antibody ameliorated cardiac fibrosis in the mouse model of angiotensin II-induced hypertension.

Conclusion: Our data indicate that IL-16 is a mediator of LV myocardial fibrosis and stiffening in HFpEF, and that the blockade of IL-16 could be a possible therapeutic option for HFpEF.

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Related in: MedlinePlus

Elevated serum interleukin-16 (IL-16) levels in patients with heart failure with preserved ejection fraction.A, Serum IL-16 levels in controls and patients with heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) measured by a multiplex-bead array assay. *P<0.05 vs. control group. †P<0.05 vs. HFrEF group. B, Serum IL-16 levels in controls and patients with HFpEF measured by enzyme-linked immunosorbent assay. C through E, Correlations of serum IL-16 level and the ratio of early transmitral flow velocity to septal mitral annular early diastolic velocity (E/e′ ratio) (C), left atrial volume index (LAVI) (D) and diastolic wall strain (DWS) (E) in controls and HFpEF patients combined.
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pone-0068893-g001: Elevated serum interleukin-16 (IL-16) levels in patients with heart failure with preserved ejection fraction.A, Serum IL-16 levels in controls and patients with heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) measured by a multiplex-bead array assay. *P<0.05 vs. control group. †P<0.05 vs. HFrEF group. B, Serum IL-16 levels in controls and patients with HFpEF measured by enzyme-linked immunosorbent assay. C through E, Correlations of serum IL-16 level and the ratio of early transmitral flow velocity to septal mitral annular early diastolic velocity (E/e′ ratio) (C), left atrial volume index (LAVI) (D) and diastolic wall strain (DWS) (E) in controls and HFpEF patients combined.

Mentions: First, we analyzed serum samples from the HFpEF and HFrEF patients and controls (Table 1) using a multiplex-bead array assay for screening the 50 cytokines, chemokines, growth factors, angiogenic factors and soluble receptors. This analysis revealed that serum IL-16 levels were significantly higher in patients with HFpEF than in patients with HFrEF or in controls (Figure 1A). Although we also found significant differences in several analytes other than IL-16 among the three groups (Table 2), we decided to focus on IL-16 because of the specific increase of IL-16 in HFpEF patients.


Interleukin-16 promotes cardiac fibrosis and myocardial stiffening in heart failure with preserved ejection fraction.

Tamaki S, Mano T, Sakata Y, Ohtani T, Takeda Y, Kamimura D, Omori Y, Tsukamoto Y, Ikeya Y, Kawai M, Kumanogoh A, Hagihara K, Ishii R, Higashimori M, Kaneko M, Hasuwa H, Miwa T, Yamamoto K, Komuro I - PLoS ONE (2013)

Elevated serum interleukin-16 (IL-16) levels in patients with heart failure with preserved ejection fraction.A, Serum IL-16 levels in controls and patients with heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) measured by a multiplex-bead array assay. *P<0.05 vs. control group. †P<0.05 vs. HFrEF group. B, Serum IL-16 levels in controls and patients with HFpEF measured by enzyme-linked immunosorbent assay. C through E, Correlations of serum IL-16 level and the ratio of early transmitral flow velocity to septal mitral annular early diastolic velocity (E/e′ ratio) (C), left atrial volume index (LAVI) (D) and diastolic wall strain (DWS) (E) in controls and HFpEF patients combined.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3716890&req=5

pone-0068893-g001: Elevated serum interleukin-16 (IL-16) levels in patients with heart failure with preserved ejection fraction.A, Serum IL-16 levels in controls and patients with heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) measured by a multiplex-bead array assay. *P<0.05 vs. control group. †P<0.05 vs. HFrEF group. B, Serum IL-16 levels in controls and patients with HFpEF measured by enzyme-linked immunosorbent assay. C through E, Correlations of serum IL-16 level and the ratio of early transmitral flow velocity to septal mitral annular early diastolic velocity (E/e′ ratio) (C), left atrial volume index (LAVI) (D) and diastolic wall strain (DWS) (E) in controls and HFpEF patients combined.
Mentions: First, we analyzed serum samples from the HFpEF and HFrEF patients and controls (Table 1) using a multiplex-bead array assay for screening the 50 cytokines, chemokines, growth factors, angiogenic factors and soluble receptors. This analysis revealed that serum IL-16 levels were significantly higher in patients with HFpEF than in patients with HFrEF or in controls (Figure 1A). Although we also found significant differences in several analytes other than IL-16 among the three groups (Table 2), we decided to focus on IL-16 because of the specific increase of IL-16 in HFpEF patients.

Bottom Line: Enhanced cardiac expression of IL-16 in transgenic mice induced cardiac fibrosis and LV myocardial stiffening accompanied by increased macrophage infiltration.Treatment with anti-IL-16 neutralizing antibody ameliorated cardiac fibrosis in the mouse model of angiotensin II-induced hypertension.Our data indicate that IL-16 is a mediator of LV myocardial fibrosis and stiffening in HFpEF, and that the blockade of IL-16 could be a possible therapeutic option for HFpEF.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.

ABSTRACT

Background: Chronic heart failure (CHF) with preserved left ventricular (LV) ejection fraction (HFpEF) is observed in half of all patients with CHF and carries the same poor prognosis as CHF with reduced LV ejection fraction (HFrEF). In contrast to HFrEF, there is no established therapy for HFpEF. Chronic inflammation contributes to cardiac fibrosis, a crucial factor in HFpEF; however, inflammatory mechanisms and mediators involved in the development of HFpEF remain unclear. Therefore, we sought to identify novel inflammatory mediators involved in this process.

Methods and results: An analysis by multiplex-bead array assay revealed that serum interleukin-16 (IL-16) levels were specifically elevated in patients with HFpEF compared with HFrEF and controls. This was confirmed by enzyme-linked immunosorbent assay in HFpEF patients and controls, and serum IL-16 levels showed a significant association with indices of LV diastolic dysfunction. Serum IL-16 levels were also elevated in a rat model of HFpEF and positively correlated with LV end-diastolic pressure, lung weight and LV myocardial stiffness constant. The cardiac expression of IL-16 was upregulated in the HFpEF rat model. Enhanced cardiac expression of IL-16 in transgenic mice induced cardiac fibrosis and LV myocardial stiffening accompanied by increased macrophage infiltration. Treatment with anti-IL-16 neutralizing antibody ameliorated cardiac fibrosis in the mouse model of angiotensin II-induced hypertension.

Conclusion: Our data indicate that IL-16 is a mediator of LV myocardial fibrosis and stiffening in HFpEF, and that the blockade of IL-16 could be a possible therapeutic option for HFpEF.

Show MeSH
Related in: MedlinePlus