During the progression of cardiomyopathy, heart failure was gradually aggravated and became the major cause of unplanned hospitalization. The mortality of heart failure is still high in the present therapy, and brain natriuretic peptide, which is elevated in acute heart failure, could be false positive in pulmonary disease, like pulmonary embolism or chronic obstructive pulmonary disease.
Metal metabolism, metalloenzymes, and their activities of oxidation and inflammation are involved in progression of heart failure [
Our study aimed to evaluate the predictive value of serum ceruloplasmin in patients with ischemic and nonischemic cardiomyopathies, and assess the association between CP levels and the extent of heart failure, CP levels and other parameters in both ischemic and nonischemic cardiomyopathy patients.
Between December 2009 and April 2011, a total of 202 patients were recruited consecutively from those who were admitted and diagnosed as heart failure patients according to New York Heart Association (NYHA) classification at the Department of Cardiology, Second Affiliated Hospital of Zhejiang University College of Medicine. Patients with advanced renal disease (serum creatinine >2 mg/dL or those on dialysis), noncardiac acute inflammatory states, known malignancies, or liver dysfunction resulting from organic hepatic diseases were excluded. However, patients with diabetes mellitus, hypercholesterolemia, hypertension, and transient liver dysfunction induced by circulatory congestion in congestive heart failure were enrolled in the study. Patients who had coronary stenosis findings in coronary angiography belonged to ischemic cardiomyopathy group, and the other patients belonged to nonischemic cardiomyopathy group. 94 subjects without organic heart disease were included in the control group. Other risk factors were balanced among three groups. The extent of heart failure is defined according to the NYHA functional classification system: NYHA I (normal)—no limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation or dyspnea; NYHA II (mild)—slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation or dyspnea; NYHA III (moderate)—marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea; NHYA IV (severe)—unable to carry out any physical activity without discomfort. Symptoms of heart failure are present at rest. If any physical activity is undertaken, discomfort increases.
All patients enrolled in the study were given informed consent, and the hospital ethics committee approved the study protocol.
For each patient, the clinical characteristics were collected, including age, gender, height, weight, history of hypertension, diabetes mellitus, cigarette smoking, and NYHA classification. Medications taken (cardiotonic, diuretic, nitrate, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker,
Echocardiography was performed for each subject and parameters were selected for analysis: LVEF (%)—left-ventricular ejection fraction, LVIDd (cm)—left-ventricular internal diameter at end diastole, and LA (cm)—left atrium.
Blood samples were collected on admission, using pyrogen-free tubes containing EDTA for plasma test and sterile tubes containing gel for serum separation (BD, USA) and then immediately centrifuged at 4000 rpm for 10 min at 4°C. All the samples were analyzed in laboratory of Second Affiliated Hospital of Zhejiang University College of Medicine. The results of blood biochemical test including total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, glucose, creatinine, C-reactive protein, troponin I, creatine kinase-MB, and CP were collected and analyzed.
The levels of serum ceruloplasmin were measured by nephelometry [
Continuous variables were given as mean ± standard deviation. Categorical variables were defined as percentage. Data were tested for normal distribution using the Kolmogorov-Smirnov test. Student’s
78 heart failure patients with coronary stenosis and 124 heart failure patients without coronary stenosis were included in ischemic and nonischemic groups, respectively. 94 subjects without heart failure were included as controls. Epidemiological characteristics and biochemical parameters of the patients according to the three groups are described in Table
Baseline characteristics of the study population between groups.
|
Control (94) | Ischemic cardiomyopathy (78) | Nonischemic cardiomyopathy (124) |
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Age (year) |
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Male sex [ |
43 (45.7%) | 40 (51.3%) |
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Smoking [ |
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Alcohol [ |
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Hypertension [ |
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Diabetes mellitus [ |
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BMI (kg/m2) |
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ALT (U/L) |
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AST (U/L) |
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Total cholesterol (mg/dL) |
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LDL-C (mg/dL) |
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Triglycerides (mg/dL) |
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Creatinine (mg/dL) |
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Uric acid (mg/dL) |
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CK (IU/l) |
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CK-MB (IU/L) |
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TNI (ng/mL) |
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CRP (mg/L) |
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Homocysteic acid ( |
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LVEF (%) |
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LVIDd (cm) |
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LA (cm) |
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Cardiac tonic [ |
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Diuretic [ |
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Nitrate [ |
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ACEI/ARB [ |
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Beta blockers [ |
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CCB [ |
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Aspirin/clopidogrel [ |
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Statins [ |
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ACEI: angiotensin-converting enzyme inhibitor; ALT: alanine aminotransferase; ARB: angiotensin receptor blocker; AST: aspartate aminotransferase; BMI: body mass index; CCB: calcium channel blocker; CK: creatinine kinase; CK-MB: creatinine kinase-MB; CRP: C-reactive protein; HDL-C: high-density lipoprotein cholesterol; LA: left atrium; LDL-C: low-density lipoprotein cholesterol; LVEF: left-ventricular ejection fraction; LVIDd: left-ventricular internal diameter at end diastole; TNI: troponin I.
*
†
To assess the relationship between ceruloplasmin and other parameters, the Pearson linear correlation was evaluated in all the subjects in Table
Linear correlation between ceruloplasmin and other parameters.
Pearson correlation |
|
|
---|---|---|
Creatinine | −0.028 | 0.635 |
ALT | 0.229 | <0.001* |
AST | 0.286 | <0.001* |
LDL-c | −0.047 | 0.428 |
Total cholesterol | −0.083 | 0.160 |
Triglycerides | −0.061 | 0.301 |
Uric acid | 0.249 | <0.001* |
CK | 0.046 | 0.435 |
CKMB | 0.037 | 0.553 |
Troponin I | 0.006 | 0.926 |
CRP | 0.449 | <0.001* |
Homocysteic acid | 0.094 | 0.107 |
LVEF | −0.151 | 0.032* |
LVIDd | 0.213 | 0.003* |
LA | 0.215 | 0.003* |
ALT: alanine aminotransferase; AST: aspartate aminotransferase; CK: creatinine kinase; CK-MB: creatinine kinase-MB; CRP: C-reactive protein; LA: left atrium; LDL-C: low-density lipoprotein cholesterol; LVEF: left-ventricular ejection fraction; LVIDd: left-ventricular internal diameter at end diastole.
*
Mean CP levels were
Ceruloplasmin levels in control, ischemic, and nonischemic cardiomyopathy groups. CP levels in ischemic and nonischemic cardiomyopathy groups were higher than those in the control group
Ceruloplasmin levels in NYHA II, NYHA III, and NYHA IV subgroups. There was no significant difference among different NYHA subgroups in ischemic cardiomyopathy patients
According to results previous mentioned, we tried to identify the relation between ceruloplasmin and the extent of heart failure in nonischemic group. All the related parameters were compared, and the results showed that AST, uric acid, CKMB, CRP, and LVEF were significantly different among NYHA II, NYHA III, and NYHA IV groups (Table
Baseline characteristics of patients with nonischemic cardiomyopathy.
Nonischemic cardiomyopathy (124) | ||||
---|---|---|---|---|
NYHA II (21) | NYHA III (71) | NYHA IV (32) |
|
|
Age (year) |
|
|
|
0.110 |
Male sex [ |
10 (47.6%) | 42 (59.2%) | 13 (40.6%) | 0.195 |
Smoking [ |
5 (23.8%) | 24 (33.8%) | 6 (18.8%) | 0.258 |
Alcohol [ |
4 (19.0%) | 15 (21.1%) | 3 (9.4%) | 0.347 |
Hypertension [ |
12 (57.1%) | 34 (47.9%) | 19 (59.4%) | 0.498 |
Diabetes mellitus [ |
4 (19.0%) | 7 (9.9%) | 7 (21.9%) | 0.225 |
BMI (kg/m2) | 21.56 |
|
|
0.639 |
ALT (U/L) | 17.33 |
|
|
0.052 |
AST (U/L) |
|
|
|
0.024* |
Total cholesterol (mg/dL) |
|
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|
0.460 |
LDL-C (mg/dL) |
|
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|
0.832 |
Triglycerides (mg/dL) |
|
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|
0.537 |
Creatinine (mg/dL) |
|
|
|
0.292 |
Uric acid (mg/dL) |
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|
0.044* |
CK (IU/L) |
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|
0.451 |
CK-MB (IU/L) |
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|
0.001* |
Troponin I (ng/mL) |
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|
0.213 |
CRP (mg/L) |
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|
0.002* |
Homocysteic acid ( |
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|
0.609 |
LVEF (%) |
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|
0.022* |
LVIDd (cm) |
|
|
|
0.101 |
LA (cm) |
|
|
|
0.434 |
Cardiac tonic [ |
6 (28.6%) | 40 (56.3%) | 22 (68.8%) | 0.017* |
Diuretic [ |
7 (33.3%) | 64 (90.1%) | 30 (93.8%) | <0.001* |
Nitrate [ |
9 (42.9%) | 49 (69.0%) | 25 (78.1%) | 0.024* |
ACEI/ARB [ |
15 (71.4%) | 64 (90.1%) | 27 (84.4%) | 0.099 |
Beta blockers [ |
12 (57.1%) | 53 (74.6%) | 18 (56.2%) | 0.107 |
CCB [ |
7 (33.3%) | 12 (16.9%) | 10 (31.2%) | 0.140 |
Aspirin/clopidogrel [ |
12 (57.1%) | 40 (56.3%) | 18 (56.2%) | 0.998 |
Statins [ |
5 (23.8%) | 14 (19.7%) | 4 (12.5%) | 0.542 |
ACEI: angiotensin-converting enzyme inhibitor; ALT: alanine aminotransferase; ARB: angiotensin receptor blocker; AST: aspartate aminotransferase; BMI: body mass index; CCB: calcium channel blocker; CK: creatinine kinase; CK-MB: creatinine kinase-MB; CRP: C-reactive protein; HDL-C: high-density lipoprotein cholesterol; LA: left atrium; LDL-C: low-density lipoprotein cholesterol; LVEF: left-ventricular ejection fraction; LVIDd: left-ventricular internal diameter at end diastole.
*
Relationship between extent of heart failure and clinical and laboratory parameters in patients with nonischemic cardiomyopathy.
Variables | OR |
|
|
95% confidence interval | |
---|---|---|---|---|---|
Lower bound | Upper bound | ||||
Age | 1.072 | 3.997 | 0.046* | 1.001 | 1.148 |
Gender | 0.293 | 1.426 | 0.232 | 0.039 | 2.198 |
Smoking | 1.499 | 0.172 | 0.678 | 0.222 | 10.136 |
Alcohol | 0.993 | 0.000 | 0.994 | 0.125 | 7.874 |
Hypertension | 2.330 | 1.214 | 0.270 | 0.518 | 10.492 |
Diabetes mellitus | 1.047 | 0.002 | 0.967 | 0.121 | 9.026 |
Creatinine | 0.157 | 1.029 | 0.310 | 0.004 | 5.609 |
ALT | 1.019 | 0.339 | 0.560 | 0.957 | 1.084 |
AST | 0.972 | 0.700 | 0.403 | 0.910 | 1.039 |
LDL-C | 1.026 | 0.481 | 0.488 | 0.954 | 1.103 |
Total cholesterol | 0.981 | 0.621 | 0.431 | 0.935 | 1.029 |
Triglycerides | 0.998 | 0.076 | 0.782 | 0.981 | 1.014 |
Uric Acid | 1.141 | 0.530 | 0.467 | 0.800 | 1.629 |
CK | 1.006 | 1.962 | 0.161 | 0.998 | 1.013 |
CKMB | 1.069 | 0.937 | 0.333 | 0.934 | 1.223 |
Troponin I | 1.304 | 1.011 | 0.315 | 0.778 | 2.185 |
CRP | 1.012 | 0.255 | 0.614 | 0.966 | 1.061 |
Homocysteic acid | 1.009 | 0.057 | 0.811 | 0.937 | 1.087 |
LVEF | 0.981 | 1.479 | 0.224 | 0.952 | 1.012 |
LVIDd | 0.616 | 0.502 | 0.479 | 0.161 | 2,354 |
LA | 0.839 | 0.097 | 0.755 | 0.280 | 2.519 |
Ceruloplasmin | 1.010 | 4.489 | 0.034* | 1.001 | 1.019 |
ALT: alanine aminotransferase; AST: aspartate aminotransferase; CK: creatinine kinase; CK-MB: creatinine kinase-MB; CRP: C-reactive protein; LA: left atrium; LDL-C: low-density lipoprotein cholesterol; LVEF: left-ventricular ejection fraction; LVIDd: left-ventricular internal diameter at end diastole. *
Ceruloplasmin (CP) is a 132-kDa plasma glycoprotein which binds 95% of the total circulating copper in healthy adults [
During the progression of heart failure, the inflammatory and oxidative reactions were activated and enhanced as a protective mechanism. So we hypothesized that CP, which was an index of the metal metabolism, still could be the inflammatory and oxidative biomarker in heart failure. The results proved our hypothesis. The CP level was elevated in patients with cardiomyopathy and showed the positive linear correlation with uric acid and C-reactive protein and negative linear correlation with left-ventricular ejection fraction, which meant that CP was increased with other acute-phase biomarkers when heart function got worse. Then we compared the CP levels of different NYHA levels in ischemic and nonischemic cardiomyopathy groups, respectively.
In ischemic heart disease, ischemic injury to cardiac muscle induced the inflammation and redox toxic reactions and the injury ran through every stage of ischemic cardiomyopathy. Copper might be involved in the redox toxic reaction [
In nonischemic cardiomyopathy patients, heart failure is always accompanied with tissue hypoxia. The hypoxia was exacerbated with low-pulse oxygen saturation clinically when heart failure was aggravated. CP synthesis was increased as a defense mechanism in response to hypoxia [
We concluded that CP levels were significantly high in patients with ischemic or nonischemic cardiomyopathy and had a positive linear correlation with C-reactive protein and a negative linear correlation with LVEF. In nonischemic cardiomyopathy patients, the CP value was an independent biomarker associated with the extent of heart failure. Further studies should be applied to confirm our data in a larger number of patients and to clarify the mechanism.
The authors declare that they have no conflict of interests.
This research was funded by the Science Technology Department of Zhejiang Province under Grant no. 2012C33028.