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Elevated Plasma Myeloperoxidase Levels in Patients with Chronic Heart Failure: Preliminary Observations
The 9th Annual Scientific Meeting
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HFSA
S121
113
115
Urotensin-II Levels Correlate with Functional Class and Systolic Function in Congestive Heart Failure Damien Gruson1, Jean-Marie Ketelslegers1, Olivier Gurne2, Sylvie A. Ahn2, Michel F. Rousseau2; 1Diabetes and Nutrition Unit, University of Louvain, Brussels, Belgium; 2 Division of Cardiology, University of Louvain, Brussels, Belgium
Proinflammatory Cytokines: TNF-alpha and IL-6, BNP and Left Ventricle Remodelling Process in Patients with Chronic Heart Failure Treated by Carvedilol Jadwiga Nessler1, Mariusz Kitlinski2, Bohdan Nessler1, Marek Stepniewski3, Wieslawa Piwowarska1; 1Dpt of Coronary Disease, Institute of Cardiology, Cracow, Poland; 2 Dpt of Cardiology, University Hospital, Malmoe, Sweden; 3Radioligand Laboratory, Institute of Pharmacy, Cracow, Poland
Background: Congestive heart failure (CHF) induces an upregulation of urotensin II (UT-II), a potent endogenous peptide, and its receptor GPR14, possibly resulting in further vascular and myocardial damage. Methods: To clarify the potential involvement of this peptide in CHF, we measured plasma concentrations of UT-II in 56 CHF patients: 28 patients with mild to moderate CHF (NYHA II, mean ejection fraction 23%) and 28 patients with severe CHF (NYHA III-IV, mean ejection fraction 18%). To provide control values for UT-II, blood samples were obtained from 36 controls. UT-II was measured by radioimmunoassay (Bachem, USA). UT-II plasma levels were 0.96 ⫾ 0.26 pg/mL in the control group. Results: In comparison with the control group, UT-II plasma levels were significantly increased in NYHA II (1.21 ⫾ 0.35 pg/mL) and in NYHA III-IV (1.57 ⫾ 0.53 pg/mL) CHF groups [p ⬍ 0.001 for both]. Moreover, UT-II plasma concentrations were significantly higher in patients with severe CHF when compared to patients with mild to moderate CHF (p ⬍ 0.004). In addition, a significant relationship (r ⫽ ⫺ 0.40, p ⬍ 0.002) between UT-II plasma levels and ejection fraction is present in the whole heart failure population (see figure). Conclusions: Our data indicate that circulating UT-II levels are significantly correlated with functional class and systolic function in patients with CHF, suggesting a pathogenic role of the UT-II system in the progression of the disease. The potential benefit of UT-II receptor antagonists remains to be determine.
Aim: To analyse changes of TNF-alpha, IL-6 and BNP levels and to establish their relationship with left ventricle (LV) remodelling process in patients (pts) with chronic heart failure (HF) treated by carvedilol. Material: 86 pts (81 males) in the age of 35–70 years (x ⫽ 56.8) with chronic, symptomatic HF, treated at least for 3 month by ACE-I and diuretics, not treated by beta-blockers. In 66 pts HF was of ischemic origin and in 20 – idiopatic. 30 pts (34.9%) were in II NYHA class and 56 pts (65.1%) – in III. Methods: In all study pts the NYHA class and TNF-alpha,IL-6 and BNP levels were analysed basicly (before start the carvedilol treatment) after 3 and 12 month therapy. The remodeling process was assessed echocardiographically and in 20 pts additionally by magnetic resonance (MRI). The statistic calculations were done using the Statistica programme. Results: The main results were listed in the table below. Changes in Main Assessed Parameters After 3 and 12 Month Carvedilol Therapy.
NYHA class TNF-alpha IL-6 (pmol/ml) BNP(pmol/ml) LVEDd (mm) LVEF(%) LVEDV (ml) LVESV (ml) LVMI LP (mm)
114 Free Immunoglobulin Light-Chains as a New Biomarker of Heart Failure Akira Matsumori1, Taiko Horii2, Takanari Nakano3, Tadashi Isomura2, Hisayoshi Suma2; 1Department of Cardiovascular Medicine, Kyoto University, Kyoto, Japan; 2 Hayama Heart Center, Hayama-cho, Kanagawa, Japan; 3Immunology Laboratory, Yamasa Corporation, Choshi, Chiba, Japan Background: Human immunoglobulin light-chain kappa and lambda, proteinic components of intact immunoglobulin, are present as free light chains (FLCs) in serum and urine due to their greater production than that of heavy chains by mature B-lymphocytes. Increased concentrations of FLCs are present in malignant plasma dyscrasia and other lymphocyte-related immuno-proliferative disorders. Although FLCs in serum is a useful clinical marker, their routine laboratory assay has been limited by their cross-reaction with light chains of intact immunoglobulins. FLCs have been shown to mediate antigen-specific, mast cell-dependent hypersensitivity-like responses. Since our recent studies suggest that mast cells and their mediators play important roles in heart failure (HF), we have measured FLCs in patients suffering from HF. Methods: Serum was obtained from 17 healthy volunteers (controls) and 63 patients in NYHA HF functional class III or IV. FLC kappa and lambda were measured using a new sandwich enzyme-linked immunosorbent assay (Yamasa Corporation, Chiba, Japan). We coated 96 well immunoplates with anti-FLC kappa or lambda monoclonal antibodies, and incubated them with horseradish peroxidase-labeled F(ab′)2 of fragment of anti-FLC kappa or lambda. The color conversion of o-phenylene diamine was measured as absorbance at 492 nm. Results: The mean ( ⫾ SD) concentration of circulating FLC kappa in 63 patients with HF was 40.8 ⫾ 39.2 mg/ml (range 17–334), significantly greater than the 28.0 ⫾ 5.3 mg/ml (range 21.4–40.4) measured in controls (p ⬍ 0.0001). The mean FLC lambda concentration was also significantly higher (93.2 ⫾ 67.9 mg/ml, range 36–429 versus 43.6 ⫾ 8.8 mg/ml, range 27.0–57.0, p ⬍ 0.005), and the FLC kappa/lambda ratio lower (0.46 ⫾ 0.14 versus 0.66 ⫾ 0.16, p ⬍ 0.0001) in patients than in controls. Conclusions: This study suggests that polyclonal B lymphocytes are activated, and that the production of FLCs is increased in HF. These observations introduce a new concept by which FLCs provide a functional link between immune cells and development of HF, and points to new investigations directed toward its pathogenesis and treatment.
Before Treatment
After 3 Month
2.7 12.2 9.4 464 68.8 28.7 96.8 67.9 204 44.8
2.3
After 12 Month 5.3 5.3 366
66.4 34.1 86.2 55.3 176 42.5
p 0.001 0.001 0.004 0.001 0.014 0.0001 0.009 0.001 0.001 0.008
The multifactorial analysis (varimax) demonstrated the relationship between TNFalpha decrease and LV function improvement after 12 month carvedilol therapy. The positive correlation was found between BNP level and LVESd (r ⫽ 0.23, p ⫽ 0.04) and negative correlation between BNP level and LVEF (r ⫽ ⫺0.22, p ⫽ 0.04). Conclusions: 1. The 12 month carvedilol therapy positively influences on the LV remodelling process related to the inflammatory cytokines levels decrease. 2. Increased BNP level in pts with HF correlates with the degree of the LV dysfunction and its decrease after carvedilol therapy correlates with LV improvement.
116 Elevated Plasma Myeloperoxidase Levels in Patients with Chronic Heart Failure: Preliminary Observations W.H. Wilson Tang1, Marie-Luise Brennan1, Kiran Philip1, Cindy E. Stevenson1, Shirley Mann1, Frederick Van Lente2, Michael Pepoy1, Stanley L. Hazen1; 1Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH; 2 Department of Clinical Pathology, Cleveland Clinic Foundation, Cleveland, OH Background: Increased oxidative stress and endothelial dysfunction are commonly observed in patients with chronic heart failure. Myeloperoxidase (MPO) is a leukocytederived enzyme that catalyzes the formation of a number of reactive oxidant species and has been implicated in the pathogenesis of atherosclerotic cardiovascular disease. The relationship between MPO and left ventricular ejection fraction (LVEF) in chronic heart failure has not been reported. Methods: We evaluated plasma MPO levels in 105 normal controls (no prior clinical history of heart failure or LV dysfunction, ageand gender-matched) and 84 patients with chronic systolic heart failure (LVEF ⬍ 50%) with varying degrees of clinical severity (mean age 65 ⫾ 14 years, 58% men, mean LVEF 29.6 ⫾ 14%, 59% ischemic). We further examined the relationship between plasma MPO levels, plasma BNP levels (Abbott AxSYM), and LVEF. Results: In our study cohort, the normal range for plasma MPO levels was 204 ⫾ 139 pM
(median 171 pM). In contrast, mean plasma MPO levels in patients with chronic systolic heart failure were elevated when compared to that of control patients (1215 ⫾ 3233 pM, median 324 pM, p ⬍ 0.01). The mean plasma MPO levels increased in parallel with increasing NYHA class (see figure). There was no significant correlation between plasma MPO levels and plasma BNP levels (log MPO vs log BNP r ⫽ ⫺ 0.15, p ⫽ 0.89) or LVEF (log MPO vs LVEF, r ⫽ ⫺ 0.068, p ⫽ 0.54). Conclusion: In our cohort of patients with chronic heart failure, plasma MPO levels were elevated when compared to that of normal controls. However, we cannot demonstrate any relationship between plasma MPO and plasma BNP levels or degree of systolic dysfunction.
•
HFSA
S121
113
115
Urotensin-II Levels Correlate with Functional Class and Systolic Function in Congestive Heart Failure Damien Gruson1, Jean-Marie Ketelslegers1, Olivier Gurne2, Sylvie A. Ahn2, Michel F. Rousseau2; 1Diabetes and Nutrition Unit, University of Louvain, Brussels, Belgium; 2 Division of Cardiology, University of Louvain, Brussels, Belgium
Proinflammatory Cytokines: TNF-alpha and IL-6, BNP and Left Ventricle Remodelling Process in Patients with Chronic Heart Failure Treated by Carvedilol Jadwiga Nessler1, Mariusz Kitlinski2, Bohdan Nessler1, Marek Stepniewski3, Wieslawa Piwowarska1; 1Dpt of Coronary Disease, Institute of Cardiology, Cracow, Poland; 2 Dpt of Cardiology, University Hospital, Malmoe, Sweden; 3Radioligand Laboratory, Institute of Pharmacy, Cracow, Poland
Background: Congestive heart failure (CHF) induces an upregulation of urotensin II (UT-II), a potent endogenous peptide, and its receptor GPR14, possibly resulting in further vascular and myocardial damage. Methods: To clarify the potential involvement of this peptide in CHF, we measured plasma concentrations of UT-II in 56 CHF patients: 28 patients with mild to moderate CHF (NYHA II, mean ejection fraction 23%) and 28 patients with severe CHF (NYHA III-IV, mean ejection fraction 18%). To provide control values for UT-II, blood samples were obtained from 36 controls. UT-II was measured by radioimmunoassay (Bachem, USA). UT-II plasma levels were 0.96 ⫾ 0.26 pg/mL in the control group. Results: In comparison with the control group, UT-II plasma levels were significantly increased in NYHA II (1.21 ⫾ 0.35 pg/mL) and in NYHA III-IV (1.57 ⫾ 0.53 pg/mL) CHF groups [p ⬍ 0.001 for both]. Moreover, UT-II plasma concentrations were significantly higher in patients with severe CHF when compared to patients with mild to moderate CHF (p ⬍ 0.004). In addition, a significant relationship (r ⫽ ⫺ 0.40, p ⬍ 0.002) between UT-II plasma levels and ejection fraction is present in the whole heart failure population (see figure). Conclusions: Our data indicate that circulating UT-II levels are significantly correlated with functional class and systolic function in patients with CHF, suggesting a pathogenic role of the UT-II system in the progression of the disease. The potential benefit of UT-II receptor antagonists remains to be determine.
Aim: To analyse changes of TNF-alpha, IL-6 and BNP levels and to establish their relationship with left ventricle (LV) remodelling process in patients (pts) with chronic heart failure (HF) treated by carvedilol. Material: 86 pts (81 males) in the age of 35–70 years (x ⫽ 56.8) with chronic, symptomatic HF, treated at least for 3 month by ACE-I and diuretics, not treated by beta-blockers. In 66 pts HF was of ischemic origin and in 20 – idiopatic. 30 pts (34.9%) were in II NYHA class and 56 pts (65.1%) – in III. Methods: In all study pts the NYHA class and TNF-alpha,IL-6 and BNP levels were analysed basicly (before start the carvedilol treatment) after 3 and 12 month therapy. The remodeling process was assessed echocardiographically and in 20 pts additionally by magnetic resonance (MRI). The statistic calculations were done using the Statistica programme. Results: The main results were listed in the table below. Changes in Main Assessed Parameters After 3 and 12 Month Carvedilol Therapy.
NYHA class TNF-alpha IL-6 (pmol/ml) BNP(pmol/ml) LVEDd (mm) LVEF(%) LVEDV (ml) LVESV (ml) LVMI LP (mm)
114 Free Immunoglobulin Light-Chains as a New Biomarker of Heart Failure Akira Matsumori1, Taiko Horii2, Takanari Nakano3, Tadashi Isomura2, Hisayoshi Suma2; 1Department of Cardiovascular Medicine, Kyoto University, Kyoto, Japan; 2 Hayama Heart Center, Hayama-cho, Kanagawa, Japan; 3Immunology Laboratory, Yamasa Corporation, Choshi, Chiba, Japan Background: Human immunoglobulin light-chain kappa and lambda, proteinic components of intact immunoglobulin, are present as free light chains (FLCs) in serum and urine due to their greater production than that of heavy chains by mature B-lymphocytes. Increased concentrations of FLCs are present in malignant plasma dyscrasia and other lymphocyte-related immuno-proliferative disorders. Although FLCs in serum is a useful clinical marker, their routine laboratory assay has been limited by their cross-reaction with light chains of intact immunoglobulins. FLCs have been shown to mediate antigen-specific, mast cell-dependent hypersensitivity-like responses. Since our recent studies suggest that mast cells and their mediators play important roles in heart failure (HF), we have measured FLCs in patients suffering from HF. Methods: Serum was obtained from 17 healthy volunteers (controls) and 63 patients in NYHA HF functional class III or IV. FLC kappa and lambda were measured using a new sandwich enzyme-linked immunosorbent assay (Yamasa Corporation, Chiba, Japan). We coated 96 well immunoplates with anti-FLC kappa or lambda monoclonal antibodies, and incubated them with horseradish peroxidase-labeled F(ab′)2 of fragment of anti-FLC kappa or lambda. The color conversion of o-phenylene diamine was measured as absorbance at 492 nm. Results: The mean ( ⫾ SD) concentration of circulating FLC kappa in 63 patients with HF was 40.8 ⫾ 39.2 mg/ml (range 17–334), significantly greater than the 28.0 ⫾ 5.3 mg/ml (range 21.4–40.4) measured in controls (p ⬍ 0.0001). The mean FLC lambda concentration was also significantly higher (93.2 ⫾ 67.9 mg/ml, range 36–429 versus 43.6 ⫾ 8.8 mg/ml, range 27.0–57.0, p ⬍ 0.005), and the FLC kappa/lambda ratio lower (0.46 ⫾ 0.14 versus 0.66 ⫾ 0.16, p ⬍ 0.0001) in patients than in controls. Conclusions: This study suggests that polyclonal B lymphocytes are activated, and that the production of FLCs is increased in HF. These observations introduce a new concept by which FLCs provide a functional link between immune cells and development of HF, and points to new investigations directed toward its pathogenesis and treatment.
Before Treatment
After 3 Month
2.7 12.2 9.4 464 68.8 28.7 96.8 67.9 204 44.8
2.3
After 12 Month 5.3 5.3 366
66.4 34.1 86.2 55.3 176 42.5
p 0.001 0.001 0.004 0.001 0.014 0.0001 0.009 0.001 0.001 0.008
The multifactorial analysis (varimax) demonstrated the relationship between TNFalpha decrease and LV function improvement after 12 month carvedilol therapy. The positive correlation was found between BNP level and LVESd (r ⫽ 0.23, p ⫽ 0.04) and negative correlation between BNP level and LVEF (r ⫽ ⫺0.22, p ⫽ 0.04). Conclusions: 1. The 12 month carvedilol therapy positively influences on the LV remodelling process related to the inflammatory cytokines levels decrease. 2. Increased BNP level in pts with HF correlates with the degree of the LV dysfunction and its decrease after carvedilol therapy correlates with LV improvement.
116 Elevated Plasma Myeloperoxidase Levels in Patients with Chronic Heart Failure: Preliminary Observations W.H. Wilson Tang1, Marie-Luise Brennan1, Kiran Philip1, Cindy E. Stevenson1, Shirley Mann1, Frederick Van Lente2, Michael Pepoy1, Stanley L. Hazen1; 1Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH; 2 Department of Clinical Pathology, Cleveland Clinic Foundation, Cleveland, OH Background: Increased oxidative stress and endothelial dysfunction are commonly observed in patients with chronic heart failure. Myeloperoxidase (MPO) is a leukocytederived enzyme that catalyzes the formation of a number of reactive oxidant species and has been implicated in the pathogenesis of atherosclerotic cardiovascular disease. The relationship between MPO and left ventricular ejection fraction (LVEF) in chronic heart failure has not been reported. Methods: We evaluated plasma MPO levels in 105 normal controls (no prior clinical history of heart failure or LV dysfunction, ageand gender-matched) and 84 patients with chronic systolic heart failure (LVEF ⬍ 50%) with varying degrees of clinical severity (mean age 65 ⫾ 14 years, 58% men, mean LVEF 29.6 ⫾ 14%, 59% ischemic). We further examined the relationship between plasma MPO levels, plasma BNP levels (Abbott AxSYM), and LVEF. Results: In our study cohort, the normal range for plasma MPO levels was 204 ⫾ 139 pM
(median 171 pM). In contrast, mean plasma MPO levels in patients with chronic systolic heart failure were elevated when compared to that of control patients (1215 ⫾ 3233 pM, median 324 pM, p ⬍ 0.01). The mean plasma MPO levels increased in parallel with increasing NYHA class (see figure). There was no significant correlation between plasma MPO levels and plasma BNP levels (log MPO vs log BNP r ⫽ ⫺ 0.15, p ⫽ 0.89) or LVEF (log MPO vs LVEF, r ⫽ ⫺ 0.068, p ⫽ 0.54). Conclusion: In our cohort of patients with chronic heart failure, plasma MPO levels were elevated when compared to that of normal controls. However, we cannot demonstrate any relationship between plasma MPO and plasma BNP levels or degree of systolic dysfunction.