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J Am Coll Cardiol, 2007; 49:2364-2370, doi:10.1016/j.jacc.2007.02.053 (Published online 1 June 2007).
© 2007 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: BIOMARKER

Prognostic Value and Echocardiographic Determinants of Plasma Myeloperoxidase Levels in Chronic Heart Failure

W.H. Wilson Tang, MD, FACC*,*, Wilson Tong, MSc*, Richard W. Troughton, MBBS{dagger}, Maureen G. Martin, RDCS*, Kevin Shrestha, AB*, Allen Borowski, RDCS*, Sue Jasper, BSN*, Stanley L. Hazen, MD, PhD, FACC*,1 and Allan L. Klein, MD, FACC*

* Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
{dagger} Christchurch School of Medicine, Christchurch, New Zealand.

Manuscript received October 17, 2006; revised manuscript received February 7, 2007, accepted February 8, 2007.

* Reprint requests and correspondence: Dr. W. H. Wilson Tang, Section of Heart Failure and Cardiac Transplantation Medicine, Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Desk F25, Cleveland, Ohio 44195. (Email: tangw{at}ccf.org).


   Abstract
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Methods
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 Discussion
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Objectives: The purpose of this study was to explore the relationship between myeloperoxidase (MPO) and cardiac structure, performance, and prognosis.

Background: Myeloperoxidase is an inflammatory marker that is elevated in patients with heart failure (HF) and cardiac dysfunction, with mechanistic links to plaque vulnerability and left ventricular (LV) remodeling.

Methods: We evaluated plasma MPO levels (CardioMPO, PrognostiX, Inc., Cleveland, Ohio) in 140 patients with chronic systolic HF (LV ejection fraction <35%) and examined the plasma MPO levels’ relationships with echocardiographic indexes of systolic and diastolic performance, as well as long-term clinical outcomes (death, cardiac transplantation, or HF hospitalization).

Results: Within the overall cohort, increasing plasma MPO levels were associated with increasing likelihood of more advanced HF (restrictive diastolic stage, right ventricular systolic dysfunction ≥3+, and tricuspid regurgitation area ≥1.8 cm2). Plasma MPO levels were predictive of long-term clinical outcomes (risk ratio [95% confidence interval] = 3.35 [1.52 to 8.86]), even after adjustment for age, LV ejection fraction, plasma B-type natriuretic peptide (BNP), creatinine clearance, or diastolic stage. In receiver-operator characteristic curve analyses, addition of MPO to BNP testing augmented the predictive accuracy of future adverse clinical events (area under the curve 0.66 for BNP only [chi-square test = 12.9, p = 0.0003], and 0.70 for BNP plus MPO [chi-square test = 15.87, p = 0.0004]).

Conclusions: In chronic systolic HF, elevated plasma MPO levels are associated with an increased likelihood of more advanced HF. Moreover, elevated plasma MPO levels within a HF subject seem to be predictive of increased adverse clinical outcomes.

Abbreviations and Acronyms
  BNP = B-type natriuretic peptide
  HF = heart failure
  IQR = interquartile range
  LV = left ventricular
  LVEF = left ventricular ejection fraction
  MPO = myeloperoxidase

Increasing data support a role for inflammation and oxidative stress in the pathophysiology of heart failure (HF) (1). There is a strong association between increased lipid peroxidation (plasma and urine F2 isoprostane levels), decreased antioxidant levels, and increased severity of HF (2,3). Endothelial dysfunction as a result of oxidative stress is associated with an increased mortality risk in patients with both ischemic and nonischemic HF (4).

Myeloperoxidase (MPO) is a leukocyte-derived enzyme that can produce a cascade of reactive oxidative species, including hypochlorous acid and other reactive oxidant species, which may ultimately lead to lipid peroxidation, direct scavenging of nitric oxide, and nitric oxide synthase inhibition (5). Recent studies suggest that plasma MPO levels are elevated in patients with chronic systolic HF (6), and elevated MPO levels provide good diagnostic value in community-based screening for cardiac dysfunction (7). In animal studies, preservation of left ventricular (LV) function has been observed in both a coronary artery ligation model (8) and an ischemia reperfusion model in MPO null mice (9), suggesting that MPO may provide a mechanistic link between inflammation, oxidant stress, and impaired cardiac remodeling.

The primary objective of this study was to determine the relationship between plasma MPO levels and cardiac structure, systolic and diastolic performance, and overall prognosis in patients with chronic systolic HF. We hypothesized that elevated levels of MPO might be observed across varying stages of cardiac dysfunction and may be predictive of long-term clinical outcomes.


   Methods
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Study design and population.   The neurohormonal substudy of the ADEPT (Assessment of Doppler Echocardiography in Prognosis and Therapy) study has been previously described (10), and was approved by the Cleveland Clinic Institutional Review Board. After informed consent, 140 ambulatory patients with stable, chronic systolic HF (LV ejection fraction [LVEF] ≤35%, New York Heart Association functional class II to IV) underwent echocardiographic evaluation of systolic and diastolic performance as well as plasma sample collection. Clinical events (all-cause mortality, cardiac transplantation, or HF hospitalization) were prospectively tracked by scheduled telephone follow-up and validated by chart review as previously described (11). Creatinine clearance was calculated using the Cockcroft-Gault equation based on creatinine, age, and weight. Plasma B-type natriuretic peptide (BNP) levels were analyzed by the Christchurch BNP assay as published previously (10), which is a well-validated radioimmunoassay with the normal range (up to the 97.5th percentile of normal patients) to be <40 pg/ml and values slightly lower than that of commercially available assays (12).

Plasma MPO assays.   All samples were collected using ethylenediaminetetraacetic acid plasma tubes, processed and frozen at –80°C until analyzed. Plasma MPO levels were determined by the CardioMPO II test (PrognostiX, Inc, Cleveland, Ohio), cleared by the U.S. Food and Drug Administration. This sandwich enzyme-linked immunosorbent assay showed a minimum detection limit (as calculated by interpolation of the mean plus 2 SDs) of 30 pM, with a within-run precision of 4.8%. For apparently healthy middle-aged patients, we have previously reported mean plasma MPO levels of 204 ± 139 pM. Accuracy studies using method of standard additions with isolated pure human MPO and multiple (n = 20) plasma samples showed overall recovery of 97.8 ± 2.7%. All laboratory analyses were performed with investigators blinded to clinical outcomes.

Transthoracic echocardiography.   Comprehensive transthoracic echocardiography was performed using commercially available HDI 5000 (Phillips Medical Systems, Bothell, Washington) and Acuson Sequoia (Siemens Medical Solutions USA Inc., Malvern, Pennsylvania) machines. Two-dimensional and color Doppler imaging was performed in standard parasternal and apical views. Diastolic indexes (including pulse-wave Doppler, color M-mode, and tissue Doppler imaging) were acquired over 10 consecutive beats using sweep speeds of 50 cm/s and 100 cm/s using previously described techniques. Classification of diastolic stage was determined as follows: Stage I (impaired relaxation) consists of mitral E/A <1, deceleration time >220 ms, pulmonary vein S/D >1, atrial reversal (AR) <35 cm/s; Stage II (pseudonormal) shows mitral E/A = 1 to 2, pulmonary vein S/D <1, deceleration time <220 ms, AR >35 cm/s; Stage III (restrictive) gives mitral E/A >2, pulmonary vein S/D <1, deceleration time <150 ms, AR >35 cm/s. Estimates for left atrial pressure were determined from pulmonary vein S/D, E/septal Ea, and mitral E/Vp ratios. The LVEF and cardiac volumes were measured using the Simpson biplane method. Measurements were averaged over 3 cycles (5 cycles for atrial fibrillation), and 2 experienced individuals who were blinded from the neurohormonal data made all measurements.

Statistical analysis.   Plasma MPO levels were non-normally distributed and were treated as nonparametric variables (expressed as median and interquartile range [IQR]). Analysis of variance or the Kruskal-Wallis test was used to assess differences in continuous clinical variables across MPO tertiles according to whether or not the distribution was normal, whereas contingency table analysis was performed to assess differences in clinical proportions across MPO tertiles. Normality was assessed by the Shapiro-Wilk W test. Systolic blood pressure, creatinine clearance, BNP, LV end-diastolic volume index, and LVEF were non-normally distributed, and age and heart rate were normally distributed. The Spearman rank correlation method was used as a nonparametric measure of association for correlations between plasma MPO levels and all clinical variables. The odds ratios of having altered systolic or diastolic performances were calculated from multivariate logistic regression across 1st, 2nd, and 3rd tertiles of MPO with respect to the 1st tertile (odds ratio = 1.0). Adjustments were made for age and BNP levels. Kaplan-Meier survival plots were calculated from baseline to time of all-cause mortality, cardiac transplantation, or HF hospitalization over a mean follow-up of 33 months. All univariate and multivariate Cox proportional hazard analyses were also calculated with all-cause mortality, cardiac transplantation, or HF hospitalization as outcome, and with plasma MPO levels treated as a categorical variable modeling differences in outcomes for patients within the highest 2 tertiles relative to the lowest of plasma MPO. Receiver-operator characteristic curve analysis was performed to determine the incremental prognostic value of MPO with BNP. A p value <0.05 was considered statistically significant. Statistical analyses were performed using SAS version 9.1 and JMP version 5.1 (SAS Institute Inc., Cary, North Carolina).


   Results
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Discussion
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In our study cohort, the mean and median plasma MPO were 431 ± 337 pM and 303 pM [IQR = 256 to 430], respectively. Table 1 illustrates the patients characteristics stratified according to plasma MPO tertiles in the overall cohort. Left ventricular ejection fraction or LV end-diastolic dimensions, as well as other clinical and laboratory data, gave no significant differences across MPO tertiles. In contrast, increasing plasma MPO levels were associated with a higher proportion of right ventricular systolic dysfunction. In multivariable stepwise logistic regression analysis using variables that showed statistically significant correlation with logarithmic transformed plasma MPO levels (Table 2), only tissue Doppler imaging-derived septal Aa wave showed an independent association with MPO levels (p = 0.01).


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  		Table 1 Patient Baseline Characteristics Across Tertiles of Plasma MPO Levels
 

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  		Table 2 Correlation Between Plasma MPO Levels and Clinical and Echocardiographic Characteristics for the Total Study Population and in the Patient Cohort With LVEF ≤25%
 
The median LVEF level in this study cohort was 26%, hence further analyses regarding more impaired systolic dysfunction were stratified according to those at or below median LVEF (<26% or ≤25%) versus those above median LVEF (>25% or ≥26%). The relationship between plasma MPO levels and echocardiographic measures of LV filling pressure and compliance (including mitral inflow E/A ratio, deceleration time, pulmonary vein S/D ratio, and tissue Doppler imaging-derived E/septal Ea ratio) seemed stronger in the LVEF ≤25% cohort compared with that in the LVEF >25% cohort (Table 2). In further examination of this relationship in patients with LVEF <20%, the correlation with MPO became even stronger, particularly for mitral E/A ratio (r = 0.56, p = 0.007), pulmonary vein S/D ratio (r = –0.57, p = 0.005), tissue Doppler imaging septal Aa (r = –0.53, p = 0.014), and diastolic stage (r = 0.49, p = 0.021). In the total population, the likelihood of detecting more advanced diastolic (diastolic stage ≥III) or right ventricular systolic dysfunction was higher with increasing tertiles of plasma MPO levels. A significantly higher percentage of patients with diastolic stage III (45% vs. 24%, p = 0.048) or RV systolic dysfunction ≥3+ (38% vs. 13%, p = 0.006) were in the 3rd MPO tertile compared with those in the 1st MPO tertile (Table 3).


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  		Table 3 Odds Ratios and 95% Confidence Intervals for the Presence of Clinical Conditions Across Increasing Myeloperoxidase Tertiles
 
After a mean follow-up of 33 ± 16 months, 23% of patients experienced death or cardiac transplantation, whereas 29% of patients had combined end points of death, transplantation, or HF hospitalization. Compared with those without clinical events, patients who died or underwent heart transplantation (median [IQR] in pM, 345 [283 to 481] vs. 290 [247 to 425], p = 0.035) and those with combined end points of death, transplantation, or HF hospitalization (median [IQR] in pM, 360 [284 to 452] vs. 289 [247 to 418], p = 0.013) had higher plasma MPO levels. Increasing tertiles of MPO were predictive of mortality and cardiac transplantation alone in the study cohort (risk ratio = 1.56 [95% confidence interval 1.01 to 2.46], p = 0.043). Figure 1A illustrates the long-term adverse clinical events (death, cardiac transplantation, or HF hospitalization) of patients with chronic systolic HF stratified by tertiles of plasma MPO levels, whereas Figure 1B compares patients within the highest 2 plasma MPO tertiles (>271 pM) relative to the lowest with each subgroup further stratified by median plasma BNP (65 pg/ml). Patients with plasma MPO levels within the upper 2 tertiles and above-median plasma BNP fared significantly worse than those with lower plasma MPO and BNP levels (Fig. 1B).


Figure 1
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  		Figure 1 Kaplan-Meier Analysis of All-Cause Death, Cardiac Transplantation, or Heart Failure Hospitalization

–/+MPO = first tertile (≤271 pM) versus second and third tertile (>271 pM) plasma MPO levels; –/+BNP = below-median versus above-median plasma BNP levels (median = 65 pg/ml). BNP = B-type natriuretic peptide; MPO = myeloperoxidase.

 
In further receiver-operator characteristic curve analysis, adding MPO to BNP testing augmented the predictive accuracy of future adverse clinical events (area under the curve increased from 0.66 for BNP only [chi-square = 12.9, p = 0.0003] to 0.70 for BNP plus MPO [chi-square = 15.87, p = 0.0004]). After individual adjustments with age, LVEF, New York Heart Association functional class, or plasma BNP levels, increasing MPO remained a significant predictor of long-term clinical events (Table 4). Also, higher MPO levels are associated with a worse prognosis when combined adjustments include LVEF, plasma BNP, and diastolic stage (risk ratio [95% confidence interval] = 2.52 [1.06 to 7.43], p = 0.036). In addition, a poorer prognosis was shown in patients with elevated plasma MPO levels (above 1st tertile) and LVEF ≤25% or restrictive LV diastolic filing pattern (Fig. 2). Stratifying plasma MPO by median levels rather than tertiles yielded similar results.


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  		Table 4 Univariate and Multivariate Cox Proportional Hazard Analyses of Death, Cardiac Transplantation, or HF Hospitalization Across MPO Tertiles
 

Figure 2
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  		Figure 2 Adverse Event Rate and Corresponding Hazard Ratios for Subgroups

Hazard ratios are calculated relative to the subgroup with the lowest risk (hazard ratio = 1.0). HF = heart failure; LVEF = left ventricular ejection fraction; MPO = myeloperoxidase.

 

   Discussion
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 Abstract
 Methods
 Results
 Discussion
Conclusions
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During inflammation, MPO is released, for which its measurement in systemic circulation may be used as an index of leukocyte activation and oxidant stress. The MPO levels correlate with cardiovascular events in patients presenting with chest pain (13) and in patients with end-stage renal diseases (14). We previously have reported the relationship between increasing plasma MPO levels and the presence of HF in the general population (15). Recent studies by Ng et al. (7) also report a potential role for initial plasma MPO testing (followed by plasma BNP and high-sensitivity C-reactive protein testing) for improved sensitivity in population screening for occult LV systolic dysfunction among apparently healthy patients. The present studies extend these initial reports, suggesting that plasma MPO levels are higher in patients with more advanced HF as determined by detailed echocardiographic examination including LV diastolic function and right ventricular systolic dysfunction, and may provide prognostic values in predicting long-term clinical outcomes, even after adjusting for commonly used prognostic variables.

Recently from a post hoc analysis of the SOLVD (Studies Of Left Ventricular Dysfunction) study, subclinical inflammation, as indicated by an increase in serial total leukocyte count and neutrophil counts, has been associated with worsening HF outcomes (16). These results also were consistent with a recent pilot study showing that increases in neutrophil count during follow-up were associated with sudden unexpected death (17). It is conceivable that chronic leukocyte activation may lead to disease progression of HF, although direct evidence is somewhat limited and largely in animal models (18,19). Our data provide a direct mechanistic link between leukocyte-driven inflammation, degree of severity of altered cardiac structure and performance, and clinical outcomes in humans. It is likely that the combination of progressive ventricular degradation and failed counterregulatory antioxidant mechanisms may contribute to elevated oxidative stress in severe left and right ventricular systolic and diastolic dysfunction.

Within the overall cohort, increasing plasma MPO levels were associated with an increasing likelihood of more restrictive (Stage III) diastolic dysfunction and more severe (>3+) right ventricular systolic dysfunction. This is consistent with animal studies showing the association of elevated MPO levels with collagen accumulation in matrix remodeling after myocardial infarction (20). Overactivation of peroxidases and generation of reactive oxygen species also are implicated in diastolic dysfunction via matrix remodeling in diabetic (21) and doxorubicin-induced (22) cardiomyopathies. These results thus may offer insight into the role of MPO-mediated oxidative stress in the progression of restrictive filling pattern and myocardial fibrosis.

Previous outcome studies also have shown that other markers of oxidative stress, such as oxidized low-density lipoprotein, catecholamine-induced adrenolutin, and malondialdehyde from lipid peroxidation, are predictive of mortality (23–25). However, measurement of these biomarkers is technically challenging. Further, these have not been shown to remain significant independent predictors of adverse outcomes even after adjustment for either LVEF or BNP levels. In the present study, the prognostic value of plasma MPO for predicting future adverse clinical events remained significant even after adjustment for both LVEF and plasma BNP levels, as well as other traditional cardiovascular risks. These observations establish the fact that plasma MPO, a commercially available immunoassay cleared by the U.S. Food and Drug Administration, may provide additive prognostic value heralding more severe underlying disease. The present results also possibly provide insight into underlying disease mechanisms, including a potential catalytic source for lipid peroxidation, cytokine activation, apoptosis, and platelet adhesion. These pathophysiological processes may be distinct from those leading to LV systolic dysfunction or BNP production, and therefore may identify a unique HF phenotype. Interestingly, the ability of diastolic and right ventricular systolic performance to diminish the prognostic value of MPO also implies a relationship between MPO-derived oxidative stress and altered diastolic and right ventricular systolic performance in the setting of chronic systolic HF. It is unclear why there is an asymmetric distribution of hazard ratios across tertiles of MPO with respect to associated echocardiographic abnormalities (Table 3) and clinical events (Fig. 1). It is conceivable that the absence of subclinical inflammation and oxidative stress represents the contributing factor to the lack of disease progression seen in this cohort of patients with chronic stable HF, and will require larger clinical trials to validate these findings.

Recently, several studies have suggested the potential benefits of statin therapy in patients with chronic HF independent of their lipid-lowering effects (26–29). Although our study population has a low rate of statin use to examine the potential influence of statins on plasma MPO levels, several multicenter mortality trials currently are underway to determine whether statin therapy improves cardiac performance and reduces morbidity and mortality in the HF patient population. The proposed underlying mechanism is complex, and may involve both enhanced nitric oxide production and reductions in cytokine production, reactive oxygen species generation, or matrix metalloproteinase activity (30–32). Shishehbor et al. (33) have shown the possibility of modulation of nitrosative stress by detecting a significant reduction in serum nitrotyrosine levels in patients without underlying cardiac dysfunction after statin therapy. Furthermore, Kumar et al. (34) recently reported that MPO expression was suppressed by statins. It is intriguing to speculate that in symptomatic patients with chronic systolic HF and with heightened plasma MPO levels (as one of the major contributors of nitrosative stress), statin therapy may provide beneficial effects via modulation of these oxidative-nitrosative stress pathways.

There are several limitations to this analysis. It is possible that underlying drug therapy may influence plasma MPO levels (such as beta-adrenergic blocker) even though the drug utilization rates across MPO tertiles were similar. Our study did not collect information regarding baseline total leukocyte counts to evaluate their prognostic values relative to plasma MPO, although prior clinical studies have reported that MPO remains an independent predictor of cardiac risks even when adjusting for leukocyte count (13). The relatively low number of clinical events may limit the ability of multivariable statistical analyses to compare the prognostic role of MPO. Despite the need to confirm our findings in larger clinical studies, the potential ability to unravel an underlying oxidative stress phenotype of chronic systolic HF is promising.


   Conclusions
Top
 Abstract
 Methods
 Results
 Discussion
 Conclusions
References
 
Higher plasma levels of MPO were associated with an increasing likelihood of greater severity of impairment of LV diastolic performance and right ventricular systolic dysfunction, and an increasing likelihood of adverse clinical events after adjustments for systolic dysfunction.


   Footnotes
 
The ADEPT study was supported by the 2003 American Society of Echocardiography Outcomes Research Award (Drs. Troughton and Klein) and by GlaxoSmithKline Pharmaceuticals. This work on myeloperoxidase in the ADEPT study was supported by National Institutes of Health grants P01 HL076491, P01 HL77107, and HL70621; the American Heart Association Ohio Valley Affiliates (0465266B); and the Cleveland Clinic Foundation General Clinical Research Center (M01 RR018390). Drs. Hazen and Tang have received research grant support from Abbott Diagnostics, Inc. Margaret Redfield, MD, acted as the Guest Editor for this article.

1 Dr. Hazen is named as co-inventor on pending patents filed by the Cleveland Clinic Foundation that relate to the use of biomarkers to inflammatory and cardiovascular diseases. Dr. Hazen is the scientific founder and a consultant to PrognostiX Inc. Dr. Hazen has received honoraria and consulting fees from PrognostiX Inc. and Biosite, Inc. Back


   References
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j.jacc.2007.02.053v1
49/24/2364    most recent
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