Elevated Circulating Levels of C-C Chemokines in Patients With Congestive Heart Failure

Aukrust, Pål; Ueland, Thor; Müller, Fredrik; Andreassen, Arne K.; Nordøy, Ingvild; Aas, Halfdan; Kjekshus, John; Simonsen, Svein; Frøland, Stig S.; Gullestad, Lars

doi:10.1161/01.cir.97.12.1136

Cited by 332 publications

(243 citation statements)

References 39 publications

(41 reference statements)

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“…To clarify the role of MCP-1 in the pathogenesis of myocarditis, we have examined the expression of MCP-1 in rat hearts with experimental autoimmune myocarditis (EAM), and have also measured serum levels of MCP-1 in patients with histology-proven acute myocarditis. Lewis rats were immunized with cardiac myosin and were killed 9,12,15,18,21,24,27,30,33, 36, 42 and 56 days after immunization. Large mononuclear cells in the myocardial interstitium were stained with an anti-MCP-1 antibody.…”

Section: Discussionmentioning

confidence: 99%

Enhanced expression and production of monocyte chemoattractant protein-1 in myocarditis

Fuse

Kodama

Hanawa

et al. 2001

Clinical and Experimental Immunology

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SUMMARYMonocyte chemoattractant protein-1 (MCP-1) is a member of the C-C chemokine family that has been shown to play a major role in the migration of monocytes and T cells to an inflammatory focus. To clarify the role of MCP-1 in the pathogenesis of myocarditis, we have examined the expression of MCP-1 in rat hearts with experimental autoimmune myocarditis (EAM), and have also measured serum levels of MCP-1 in patients with histology-proven acute myocarditis. Lewis rats were immunized with cardiac myosin and were killed 9,12,15,18,21,24,27,30,33, 36, 42 and 56 days after immunization. Large mononuclear cells in the myocardial interstitium were stained with an anti-MCP-1 antibody. mRNA of MCP-1 increased in the hearts of EAM rats from days 15±27 as shown by quantitative reverse transcription-polymerase chain reaction. Serum MCP-1 levels of the rats with EAM were significantly elevated from days 15±24. In the clinical study, serum levels of MCP-1 in 24 patients with acute myocarditis at the time of admission (165´2^55´8 pg/ml) were significantly (P 0´0301) elevated compared with those of 20 healthy volunteers (61´8^10´7 pg/ml). Serum MCP-1 levels of 8 fatal cases (371´8^145´2 pg/ml) were significantly (P 0´0058) higher than those of 16 cases who survived (65´5^12´8 pg/ml). In conclusions, MCP-1 may play an important role in the pathogenesis of human acute myocarditis as well as in the progression of rat EAM.

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Section: Discussionmentioning

confidence: 99%

Enhanced expression and production of monocyte chemoattractant protein-1 in myocarditis

Fuse

Kodama

Hanawa

et al. 2001

Clinical and Experimental Immunology

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“…CXCR4 is one of several chemokine receptors that are up-regulated in patients with heart failure [2,6,7]. To our knowledge, it is the only chemokine receptor that has been shown to be upregulated in the failing myocardium of patients by direct staining [6].…”

Section: Introductionmentioning

confidence: 98%

“…Chemokines and their receptors are up-regulated in patients with heart failure and therefore have been implicated in the development of this disease (reviewed in [1]). Contractile dysfunction is a prominent feature in heart failure, and there is an inverse relationship between chemokine levels and cardiac performance [2]. However, it is unclear whether these findings are merely coincidental or whether chemokines actually play a mechanistic role in mediating myocardial dysfunction.…”

Section: Introductionmentioning

confidence: 99%

CXCR4 modulates contractility in adult cardiac myocytes

Pyo¹,

Sui²,

Dhume³

et al. 2006

Journal of Molecular and Cellular Cardiology

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The inflammatory response is critical to the development and progression of heart failure. Chemokines and their receptors are a distinct class of inflammatory modulators that may play a role in mediating myocardial dysfunction in heart failure. Levels of the chemokine CXCL12, also known as stromal cell-derived factor (SDF), and its receptor, CXCR4, are elevated in patients with heart failure, and we undertook this study to determine whether this chemokine system can directly affect cardiac function in the absence of leukocytes. Murine papillary muscles and adult rat cardiac myocytes treated with CXCL12, the only identified ligand of CXCR4, demonstrate blunted inotropic responses to physiologic concentrations of calcium. The negative inotropic effects on cardiac myocytes are accompanied by a proportional diminution of calcium transients. The effects are abrogated by AMD3100, a specific CXCR4 inhibitor. Overexpression of the receptor through adenoviral infection with a CXCR4 construct accentuates the negative inotropic effects of CXCL12 on cardiac myocytes during calcium stimulation. CXCR4 activation also attenuates beta-adrenergicmediated increases in calcium mobilization and fractional shortening in cardiac myocytes. In electrophysiologic studies, CXCL12 decreases forskolin-and isoproterenol-induced voltage-gated L-type calcium channel activation. These studies demonstrate that activation of CXCR4 results in a direct negative inotropic modulation of cardiac myocyte function. The specific mechanism of action involves alterations of calcium channel activity on the membrane. The presence of functional CXCR4 on cardiac myocytes introduces a new target for treating cardiac dysfunction.

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“…It has been proposed that a heightened pro‐inflammatory state may play a role in the progression of HF, including acute decompensations 1, 2, 3, 4, 5, 6, 7, 8, 9. Impairment of nitric oxide bioavailability due to oxidative stress, leading to impaired cyclic guanosine monophosphate‐protein kinase G signaling29 is one potential mechanism underlying the link between inflammation and HF progression.…”

Section: Introductionmentioning

confidence: 99%

Pro‐Inflammatory Biomarkers in Stable Versus Acutely Decompensated Heart Failure With Preserved Ejection Fraction

Abernethy

Raza

Sun

et al. 2018

JAHA

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BackgroundUnderlying inflammation has been increasingly recognized in heart failure with a preserved ejection fraction (HFpEF). In this study we tested the hypothesis that pro‐inflammatory biomarkers are elevated in patients with acutely decompensated HFpEF (AD‐HFpEF) compared with patients with stable HFpEF (S‐HFpEF).Methods and ResultsUsing a post hoc analysis the serum biomarkers tumor necrosis factor‐alpha, high‐sensitivity C‐reactive protein interleukin 6 and pentraxin 3 (PTX3) and clinical, demographic, echocardiographic‐Doppler and clinical outcomes data were analyzed in HFpEF patients enrolled in NHLBI Heart Failure Research Network clinical trials which enrolled patients with either AD‐HFpEF or S‐HFpEF. Compared to S‐HFpEF, AD‐HFpEF patients had higher levels of PTX3 (3.08 ng/mL versus 1.27 ng/mL, P<0.0001), interleukin‐6 (4.14 pg/mL versus 1.71 pg/mL, P<0.0001), tumor necrosis factor‐alpha (11.54 pg/mL versus 8.62 pg/mL, P=0.0015), and high‐sensitivity C‐reactive protein (11.90 mg/dL versus 3.42 mg/dL, P<0.0001). Moreover, high‐sensitivity C‐reactive protein, interleukin‐6 and PTX3 levels were significantly higher in AD‐HFpEF compared with S‐HFpEF patients admitted for decompensated HF within the previous year. PTX3 was positively correlated with left atrial volume index (r=0.41, P=0.0017) and left ventricular mass (r=0.26, P=0.0415), while tumor necrosis factor‐alpha was inversely correlated with E/A ratio (r=−0.31, P=0.0395).ConclusionsLevels of pro‐inflammatory biomarkers are strikingly higher in AD‐HFpEF compared with S‐HFpEF patients. PTX3 and tumor necrosis factor‐alpha are correlated with echocardiographic‐Doppler evidence of diastolic dysfunction. Taken together these data support the concept that a heightened pro‐inflammatory state has a pathophysiologic role in the development of AD‐HFpEF.

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Elevated Circulating Levels of C-C Chemokines in Patients With Congestive Heart Failure

Abstract: This first demonstration of increased circulating levels of C-C chemokines in CHF with particularly high levels in patients with severe disease may represent previously unrecognized pathogenic factors in CHF.

Cited by 332 publications

References 39 publications

Enhanced expression and production of monocyte chemoattractant protein-1 in myocarditis

Enhanced expression and production of monocyte chemoattractant protein-1 in myocarditis

CXCR4 modulates contractility in adult cardiac myocytes

Pro‐Inflammatory Biomarkers in Stable Versus Acutely Decompensated Heart Failure With Preserved Ejection Fraction

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