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Elevated Urinary Neopterin Levels Are Associated with Cardiac and Functional Impairment in Patients with Chronic Systolic Heart Failure
S28 Journal of Cardiac Failure Vol. 17 No. 8S August 2011 carbamylation, with cardio-renal function and long-term outcomes in chronic systolic heart failure. Methods: In 115 patients with chronic systolic HF (LVEF!35%, NYHA II-IV), we measured plasma PB HCit by quantitative mass spectrometry and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse long-term events (death, transplant) were tracked for 5 years. Results: In our study cohort (age 57614 years; LVEF 2666%, median BUN 20 mg/dL, median NT-proBNP 1252 pg/mL), median PB HCit level was 87 [IQR: 59, 128] mmol/mol Lys. PB Hcit levels were higher in males (97 [51, 138] vs 78 [44, 93] mmol/mol Lys, p50.021) and diabetes mellitus (117 [74,156] vs 82 [58,115], p50.022). Higher plasma PB Hcit levels were associated with poorer renal function (eGFR Spearman’s r5 -0.37, p!0.001; cystatin C r50.31, p50.001), and elevated plasma NT-proBNP levels (r5 0.26, 0.006), but not with markers of systemic inflammation or oxidant stress (hsCRP and MPO, pO0.10 for both). Elevated plasma PB HCit levels were not related to indices of cardiac structure or function (pO0.10 for all) except modestly with increased right atrial volume index (RAVi; r50.31, p50.002). PB HCit levels predicted adverse long-term events (HR: 1.8, 95% CI 1.3- 2.6, p!0.001) independent of age, eGFR, MPO and NT-proBNP (HR: 1.9, 95% CI: 1.2-3.1, p50.006).
090 Gut-Flora-Dependent Phosphatidylcholine Metabolites Predict Adverse Clinical Outcomes in Chronic Systolic Heart Failure Kevin Shrestha1, Zeneng Wang1, Allen G. Borowski1, Richard W. Troughton2, Allan L. Klein1, Stanley L. Hazen1, W.H. Wilson Tang1; 1Cleveland Clinic, Cleveland, OH; 2 Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand Introduction: Three gut-flora generated metabolites of the dietary lipid phosphatidylcholine e Trimethylamine N-oxide (TMANO), choline and betaine e have been linked to increased risk for cardiovascular disease in stable patients undergoing elective cardiac evaluation. The relationships of these metabolites to myocardial indices and long-term clinical prognosis in chronic systolic heart failure have not been examined. Methods: In 112 patients with chronic systolic HF (LVEF!35%, NYHA I-IV) with comprehensive echocardiographic evaluation, we measured plasma TMANO, choline, and betaine by mass spectrometry. Adverse long-term events (death, cardiac transplantation) were tracked for 5 years. Results: In our study cohort (age 57614 years; LVEF 2666%, median NT-proBNP 1,473 pg/mL, eGFR 70626 mL/ min/1.73 m2), median TMANO levels were 5.8 [3.6, 12.1] mM, median choline 109.9 [8.4, 14.0] mM, and median betaine 43.8 [37.1, 53.0] mM. Choline levels were positively correlated with both TMANO and betaine (p!0.0001 for both). TMANO levels were significant higher in patients with diabetes mellitus (9.4 [4.9, 13.2] vs 4.8 [3.4, 9.8] mM, p50.005) and in NYHA class $ III (7.0 [4.7, 14.8] vs 4.7 [3.4, 11.3] mM, p50.02). Elevated TMANO, choline, and betaine levels were each associated with higher plasma NT-proBNP levels and more advanced left ventricular (LV) diastolic but not systolic dysfunction. Gut-flora-Dependent Phosphatidylcholine Metabolites, Age, and Cardiac Indices
Age LV ejection fraction Mitral E/septal Ea LA volume index NT-proBNP
Choline
Betaine
TMANO
0.26 -0.10 0.33 0.45 0.45
0.09 -0.19 0.29 * 0.22 * 0.27 **
0.12 0.09 0.29 ** 0.29 ** 0.26 **
** ** ** **
* p!0.05; ** p!0.01
Conclusions: In chronic systolic HF, protein carbamylation is associated with poorer renal but not cardiac function, and portends poorer long-term adverse clinical outcomes even when adjusted for cardio-renal indices.
Higher choline, betaine and TMAO levels each predicted increased risk for long-term adverse clinical events (Choline: Hazard ratio (HR) 1.64 [95% CI: 1.22 e 2.20], p50.001; Betaine: HR 1.51 [1.10-2.08], p50.011; TMANO: HR 1.48 [1.10-1.96], p50.010). Higher TMANO levels predicted adverse clinical events independent of age, eGFR, mitral E/septal Ea, and NT-proBNP levels (HR 1.46 [1.03 e 2.14], p50.031). Conclusions: In chronic systolic HF, elevated plasma TMANO, choline and betaine levels are associated with more advanced LV diastolic dysfunction and portend poorer long-term adverse clinical outcomes. Higher plasma TMANO levels predict poor prognosis even after adjustment for cardio-renal indices.
091
089 Elevated Urinary Neopterin Levels Are Associated with Cardiac and Functional Impairment in Patients with Chronic Systolic Heart Failure Zhili Shao1, Renliang Zhang1, Allen G. Borowski1, Akanksha Thakur2, W.H. Wilson Tang1; 1Cleveland Clinic, Cleveland, OH; 2Case Western Reserve University, Cleveland, OH Background: Neopterin is synthesised by macrophages upon stimulation with g-interferon and high neopterin production is associated with increased production of reactive oxygen species (oxidant stress). Circulating neopterin level predicts the risks of heart failure (HF) and death in patients with acute coronary syndromes. But the value of urinary neopterin level in HF patients has not been determined. Methods: 50 ambulatory patients with chronic systolic HF (left ventricular ejection fraction [LVEF] #45%) underwent comprehensive echocardiographic evaluation and cardiopulmonary exercise test. Urinary neopterin levels were quantified by LC/MS/MS analysis. Urine pterins were separated by high-performance liquid chromatography (HPLC). Tandem mass spectrometric (MS) analyses were then performed online in the positive ion mode using parent/daughter ion transition (254/206) and retention time unique for neopterin. Urine creatinine (Cr) levels were measured by Abbott Architect assay. Results: In our study cohort (mean age 52613 years, 80% male, mean LVEF 3066%), median urinary neopterin level was 55.55 (interquartile range 39.39-81.39) mmol/mol Cr. There were significant correlations between urinary neopterin levels and abnormalities in cardiac structure and function by echocardiography: LVEF (r5 -0.3629, p50.0096), LVEDVi (r5 0.3538, p50.0136), LVESVi (r5 0.3977, p50.0051), and E/septal Ea (r5 0.3266, p50.022). Although there was no significant correlation was seen between urinary neopterin and peak oxygen consumption (peak VO2, r5-0.2087, p50.1501), there was a direct correlation between urine neopterin and ventilatory efficiency (VE/VCO2 slope, r50.3697, p50.0089). Conclusion: In patients with chronic systolic heart failure, elevated urinary neopterin levels are associated with the severity of cardiac dysfunction.
Do Cytokines and Biomarkers Play a Role on Cognitive Impairment in Heart Failure? Ponrathi R. Athilingam1, Leway Chen2; 1University of South Florida, Tampa, FL; 2 University of Rochester, Rochester, NY Introduction: Heart failure (HF) patients have four times the risk for cognitive impairment compared to the general population. In our primary cross-sectional study of 90 adults with HF, 54% had mild cognitive impairment with scores below 26 on the Montreal Cognitive Assessment (MoCA), a one page scale approved for screening mild cognitive impairment. However, no association between MoCA scores and cardiac variables including cardiac index, ejection fraction, and cerebral perfusion pressure were identified. In the Framingham Heart Study, cytokines were associated with decreased memory. However, research on cytokines and cognition in HF is still infancy. Aim: Aim of this ancillary research was to examine associations between cognitive impairment and tumor necrosis factor (TNF-alpha), interleukin (IL-6), and C-reactive protein (CRP) in HF patients. Method: A-cross sectional study enrolled 38 subjects with HF aged 50 and above who met the inclusion criteria. This ancillary study followed the same protocol as our primary study and included blood samples for cytokines. Results: Participants were predominantly men (68%), Age 50 to 89 (62 6 9 years), Caucasian (79%). Seventy nine percent had ejection fraction below 40%. A total of 55% scored below 26 on the MoCA indicating mild cognitive impairment with mean score of 24.86 6 2.81. Hierarchical multiple regressions analysis yielded no statistical significance between MoCA score and cytokines. However, a marginally significant inverse relationship was identified between MoCA score and IL-6 controlling for covariates as seen in table below. Table 1. Summary of the Multiple Regression Model
Step 1 Covariates CRP TNF-alpha IL-6
R
R2
SE
R2 Change
F change
p
.662 .711 .689 .714
.438 .505 .475 .510
2.38 2.556 2.557 2.471
.438 .047 .017 .052
13.628 2.878 .980 3.163
.001 .100 .330 .085
090 Gut-Flora-Dependent Phosphatidylcholine Metabolites Predict Adverse Clinical Outcomes in Chronic Systolic Heart Failure Kevin Shrestha1, Zeneng Wang1, Allen G. Borowski1, Richard W. Troughton2, Allan L. Klein1, Stanley L. Hazen1, W.H. Wilson Tang1; 1Cleveland Clinic, Cleveland, OH; 2 Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand Introduction: Three gut-flora generated metabolites of the dietary lipid phosphatidylcholine e Trimethylamine N-oxide (TMANO), choline and betaine e have been linked to increased risk for cardiovascular disease in stable patients undergoing elective cardiac evaluation. The relationships of these metabolites to myocardial indices and long-term clinical prognosis in chronic systolic heart failure have not been examined. Methods: In 112 patients with chronic systolic HF (LVEF!35%, NYHA I-IV) with comprehensive echocardiographic evaluation, we measured plasma TMANO, choline, and betaine by mass spectrometry. Adverse long-term events (death, cardiac transplantation) were tracked for 5 years. Results: In our study cohort (age 57614 years; LVEF 2666%, median NT-proBNP 1,473 pg/mL, eGFR 70626 mL/ min/1.73 m2), median TMANO levels were 5.8 [3.6, 12.1] mM, median choline 109.9 [8.4, 14.0] mM, and median betaine 43.8 [37.1, 53.0] mM. Choline levels were positively correlated with both TMANO and betaine (p!0.0001 for both). TMANO levels were significant higher in patients with diabetes mellitus (9.4 [4.9, 13.2] vs 4.8 [3.4, 9.8] mM, p50.005) and in NYHA class $ III (7.0 [4.7, 14.8] vs 4.7 [3.4, 11.3] mM, p50.02). Elevated TMANO, choline, and betaine levels were each associated with higher plasma NT-proBNP levels and more advanced left ventricular (LV) diastolic but not systolic dysfunction. Gut-flora-Dependent Phosphatidylcholine Metabolites, Age, and Cardiac Indices
Age LV ejection fraction Mitral E/septal Ea LA volume index NT-proBNP
Choline
Betaine
TMANO
0.26 -0.10 0.33 0.45 0.45
0.09 -0.19 0.29 * 0.22 * 0.27 **
0.12 0.09 0.29 ** 0.29 ** 0.26 **
** ** ** **
* p!0.05; ** p!0.01
Conclusions: In chronic systolic HF, protein carbamylation is associated with poorer renal but not cardiac function, and portends poorer long-term adverse clinical outcomes even when adjusted for cardio-renal indices.
Higher choline, betaine and TMAO levels each predicted increased risk for long-term adverse clinical events (Choline: Hazard ratio (HR) 1.64 [95% CI: 1.22 e 2.20], p50.001; Betaine: HR 1.51 [1.10-2.08], p50.011; TMANO: HR 1.48 [1.10-1.96], p50.010). Higher TMANO levels predicted adverse clinical events independent of age, eGFR, mitral E/septal Ea, and NT-proBNP levels (HR 1.46 [1.03 e 2.14], p50.031). Conclusions: In chronic systolic HF, elevated plasma TMANO, choline and betaine levels are associated with more advanced LV diastolic dysfunction and portend poorer long-term adverse clinical outcomes. Higher plasma TMANO levels predict poor prognosis even after adjustment for cardio-renal indices.
091
089 Elevated Urinary Neopterin Levels Are Associated with Cardiac and Functional Impairment in Patients with Chronic Systolic Heart Failure Zhili Shao1, Renliang Zhang1, Allen G. Borowski1, Akanksha Thakur2, W.H. Wilson Tang1; 1Cleveland Clinic, Cleveland, OH; 2Case Western Reserve University, Cleveland, OH Background: Neopterin is synthesised by macrophages upon stimulation with g-interferon and high neopterin production is associated with increased production of reactive oxygen species (oxidant stress). Circulating neopterin level predicts the risks of heart failure (HF) and death in patients with acute coronary syndromes. But the value of urinary neopterin level in HF patients has not been determined. Methods: 50 ambulatory patients with chronic systolic HF (left ventricular ejection fraction [LVEF] #45%) underwent comprehensive echocardiographic evaluation and cardiopulmonary exercise test. Urinary neopterin levels were quantified by LC/MS/MS analysis. Urine pterins were separated by high-performance liquid chromatography (HPLC). Tandem mass spectrometric (MS) analyses were then performed online in the positive ion mode using parent/daughter ion transition (254/206) and retention time unique for neopterin. Urine creatinine (Cr) levels were measured by Abbott Architect assay. Results: In our study cohort (mean age 52613 years, 80% male, mean LVEF 3066%), median urinary neopterin level was 55.55 (interquartile range 39.39-81.39) mmol/mol Cr. There were significant correlations between urinary neopterin levels and abnormalities in cardiac structure and function by echocardiography: LVEF (r5 -0.3629, p50.0096), LVEDVi (r5 0.3538, p50.0136), LVESVi (r5 0.3977, p50.0051), and E/septal Ea (r5 0.3266, p50.022). Although there was no significant correlation was seen between urinary neopterin and peak oxygen consumption (peak VO2, r5-0.2087, p50.1501), there was a direct correlation between urine neopterin and ventilatory efficiency (VE/VCO2 slope, r50.3697, p50.0089). Conclusion: In patients with chronic systolic heart failure, elevated urinary neopterin levels are associated with the severity of cardiac dysfunction.
Do Cytokines and Biomarkers Play a Role on Cognitive Impairment in Heart Failure? Ponrathi R. Athilingam1, Leway Chen2; 1University of South Florida, Tampa, FL; 2 University of Rochester, Rochester, NY Introduction: Heart failure (HF) patients have four times the risk for cognitive impairment compared to the general population. In our primary cross-sectional study of 90 adults with HF, 54% had mild cognitive impairment with scores below 26 on the Montreal Cognitive Assessment (MoCA), a one page scale approved for screening mild cognitive impairment. However, no association between MoCA scores and cardiac variables including cardiac index, ejection fraction, and cerebral perfusion pressure were identified. In the Framingham Heart Study, cytokines were associated with decreased memory. However, research on cytokines and cognition in HF is still infancy. Aim: Aim of this ancillary research was to examine associations between cognitive impairment and tumor necrosis factor (TNF-alpha), interleukin (IL-6), and C-reactive protein (CRP) in HF patients. Method: A-cross sectional study enrolled 38 subjects with HF aged 50 and above who met the inclusion criteria. This ancillary study followed the same protocol as our primary study and included blood samples for cytokines. Results: Participants were predominantly men (68%), Age 50 to 89 (62 6 9 years), Caucasian (79%). Seventy nine percent had ejection fraction below 40%. A total of 55% scored below 26 on the MoCA indicating mild cognitive impairment with mean score of 24.86 6 2.81. Hierarchical multiple regressions analysis yielded no statistical significance between MoCA score and cytokines. However, a marginally significant inverse relationship was identified between MoCA score and IL-6 controlling for covariates as seen in table below. Table 1. Summary of the Multiple Regression Model
Step 1 Covariates CRP TNF-alpha IL-6
R
R2
SE
R2 Change
F change
p
.662 .711 .689 .714
.438 .505 .475 .510
2.38 2.556 2.557 2.471
.438 .047 .017 .052
13.628 2.878 .980 3.163
.001 .100 .330 .085