Summary
Background
Cystatin C, which has long been regarded as a biomarker that indicates kidney functions, has recently been recognized as an inflammatory marker in the human body.
Aim
To elucidate how cystatin C is related to the prognosis of systolic heart failure patients.
Methods
Patients with systolic heart failure who were admitted to the fourth affiliated hospital of Harbin Medical University between January and April 2008 were enrolled in this study. Serum homocysteine, high-sensitivity C-reactive protein (hs-CRP) and cystatin C levels were determined and all the patients received an average of 2 years of follow-up for occurrence of death, heart transplantation or readmission with worsening heart failure.
Results
Of 138 patients enrolled, those who experienced adverse outcomes (e.g. cardiac death, heart transplantation or progressive heart failure) ( n = 21) had considerably higher mean levels of serum homocysteine (28.6 ± 13.4 vs 14.4 ± 6.3 mg/L; P < 0.01), hs-CRP (17.5 ± 14.1 vs 6.4 ± 7.7 μmol/L; p < 0.01) and cystatin C (1.63 ± 0.81 vs 0.91 ± 0.27 mg/L; P < 0.01) than those without adverse outcomes ( n = 117). Furthermore, the Cox proportional hazards model demonstrated that serum homocysteine, hs-CRP and cystatin C are all independent predictors of adverse outcomes.
Conclusions
Cystatin C, together with hs-CRP and homocysteine, is an independent risk factor that is important in the prognosis of patients with systolic heart failure.
Résumé
Objectifs
La cystatine C est un biomarqueur d’évaluation de la fonction rénale, habituellement évalué par la créatinine mais a été considéré récemment comme un marqueur de l’inflammation chez l’homme. Cependant, la relation entre taux de cystatine C et pronostic de l’insuffisance cardiaque reste non élucidée.
Méthode
Cent trente-huit patients, insuffisants cardiaques, admis à l’hôpital Harbin en 2008, ont été inclus dans l’étude. Les taux sériques d’homocystéine, de CRPus et de cystatine C ont été mesurés chez tous les patients, qui ont été suivis pendant une durée moyenne de deux ans, avec prise en considération des évènements suivants : décès, transplantation cardiaque et réadmission pour aggravation de l’insuffisance cardiaque.
Résultats
Les patients ayant présenté une complication avaient des taux significativement plus élevés d’homocystéine sérique, de CRPus et cystatine C comparativement aux patients n’ayant pas présenté d’évènement cardiovasculaire (taux d’homocystéine 28,6 ± 13,4 versus 14,4 ± 6,3 mg/l, p < 0,01 ; CRPus 17,5 ± 14,1 versus 6,4 ± 7,7, p < 0,01 ; cystatine C 1,63 ± 0,81 versus 0,91 ± 0,27 mg/L, p < 0,01). De plus, le modèle de Cox a montré que les taux sériques et d’homocystéine, de CRPus et de cystatine C étaient tous des prédicteurs indépendants de la survenue de complications cardiovasculaires.
Conclusion
La cystatine, ainsi que la CRPus et l’homocystéine sont des prédicteurs indépendants d’évènements cardiovasculaires et sont associés au pronostic chez les patients insuffisants cardiaques.
Abbreviations
ACE
angiotensin-converting enzyme
ARB
angiotensin receptor blocker
BNP
B natriuretic peptide
CI
confidence interval
HDL
high-density lipoprotein
HR
hazard ratio
hs-CRP
high-sensitivity C-reactive protein
LDL
low-density lipoprotein
LVEF
left ventricular ejection fraction
NT-ProBNP
N-terminal prohormone brain natriuretic peptide
NYHA
New York Heart Association
Background
Heart failure is the end stage of heart disease. It is usually irreversible, and is characterized by high mortality. The methods used to treat or manage heart failure (such as heart transplantation and stem-cell transplantation) have only limited effects , indicating that heart failure does not merely cause damage to the heart, but that it is a systematic disease. For this reason, the above-mentioned methods cannot represent a complete cure. In the past two decades, scholars have realized that oxidative stress is one of the most important causes of heart failure because the biomarkers of oxidative stress are extremely high in patients suffering from heart failure compared to healthy individuals . Furthermore, treatments focused on oxidative stress can relieve symptoms and increase the cardiac function in both heart failure patients and animal models . The levels of these biomarkers are thought to be highly valuable for the evaluation of the severity of heart failure and the effectiveness of treatments. Such biomarkers include thiobarbituric acid-reactive substances and 8-iso-prostaglandin F2alpha .
Cystatin C is one of the most frequently studied biomarkers that indicate the level of oxidative stress in the human body; and is closely related to heart disease. Lee et al. found that patients with coronary artery disease exhibit increased serum cystatin C levels . The same observation is evident among patients with hypertension . However, the manner by which cystatin C is related to systolic heart failure and its prognosis remains unknown. We hypothesized that patients experiencing systolic heart failure would have higher cystatin C levels, and that cystatin C exhibits an inverse relationship with the prognosis of systolic heart failure. We therefore measured cystatin C levels in patients with systolic heart failure. We also followed these patients for an average of 2 years to verify our hypothesis.
Methods
Study population
Consecutive patients with either chronic or new-onset systolic heart failure (effort dyspnoea or echocardiographic findings of systolic dysfunction) who were admitted to our hospital between January and April 2008 were screened for inclusion into this prospective study. The significance of heart failure was determined by both echocardiography and NYHA classification. Only patients who successfully underwent serum hs-CRP, homocysteine and cystatin C measurements besides regular examinations (e.g. blood test, echocardiogram, electrocardiogram, etc.) qualified for inclusion. Exclusion criteria included significant valvular heart disease, active myocarditis, known congenital heart disease, recent acute coronary syndrome (within 6 months), pending revascularization, uncontrolled hypertension, and/or significant endocrine, hepatic, renal or inflammatory disease. All female patients were postmenopausal and not taking any hormone replacement therapy.
Left ventricular ejection fraction
The Vivid 7 color Doppler ultrasonic (GE Healthcare, Shanghai, China) was used for the evaluation of cardiac function. The left ventricular endocardial borders were recorded from the projected left ventriculogram in end systole and diastole. Ejection fractions of patients were confirmed by echocardiographic assessment.
Laboratory tests
After an overnight fast (≥ 12 h), blood samples were obtained from all patients after bed rest for 15 min in a quiet room in the morning hours before enrolment as described previously . Homocysteine, hs-CRP, cystatin C, total serum bilirubin, total cholesterol, triglycerides, LDL and HDL were measured and recorded for analysis.
Long-term follow-up
All patients underwent long-term follow-up. Periodical physical examinations were performed every 3 months either at home or in the hospital. Blood tests were performed at the same time. To achieve a maximum follow-up duration of 3 years, vital signs (blood pressure and heart rate) were determined for all enrolled patients as of April 2008. During long-term follow-up, the adverse outcomes defined as primary endpoints were: (1) death from cardiac causes (defined as sudden cardiac death or death resulting from progressive pump failure); (2) development or progression of heart failure that required hospitalization for an intravenous treatment of heart failure within the first 3 days after admission; or (3) heart transplantation. For patients experiencing > 1 adverse outcome, only the first one was considered. All information regarding potential adverse outcomes was acquired by review of source data, including hospital record forms, death certificates and other original documents. Other vascular events, such as stroke, nonfatal myocardial infarction or coronary revascularization, were also assessed, but not included into the outcome analysis. Medical therapy, including ACE inhibitors, angiotensin receptor blockers, beta-blockers and lipid-lowering drugs was documented.
Statistics analysis
SPSS 17.0 software was used to analyze the data. Results are reported as group means ± standard deviation (SD). A one-way ANOVA was used to determine differences among the group means. Differences at P < 0.05 were considered significant. Cumulative adverse outcome rates were estimated by Kaplan-Meier survival curves and compared by the log-rank test. For survival analysis, patients were split into two groups, based on the median values, for each of serum homocysteine, hs-CRP and cystatin C. Cox proportional hazards regression analysis was used to analyze follow-up data. Among all the variables tested, only those with statistical significance set at P < 0.05 at univariate analysis were included in a multivariable Cox regression model to determine independent predictors of adverse outcomes.
Results
Patient characteristics
Of 168 patients screened, 138 met the inclusion criteria and had complete clinical data. The mean follow-up time was 2 years (range 0.3–3 years). During follow-up, 32 adverse outcomes in 21 patients were documented: 10 patients died of cardiac causes (seven sudden death and three refractory heart failure); two patients received heart transplantation and survived until the end of follow-up; and nine had exacerbation of heart failure as observed in the worsening of NYHA functional class and required re-hospitalization and intravenous treatment for heart failure. Eleven patients suffered from one adverse outcome, nine patients from two adverse outcomes, one from three adverse outcomes. No patients died of non-cardiac causes.
Patient characteristics and clinical outcomes are shown in Table 1 . The proportion of patients receiving pharmacological agents such as ACE inhibitors, ARBs, beta blockers, digoxin and statins did not differ significantly among the groups with and without adverse outcomes.
| All patients ( n = 138) | Patients without adverse outcomes ( n = 117) | Patients with adverse outcomes ( n = 21) | |
|---|---|---|---|
| Age (years) | 65.4 ± 11.0 | 64.1 ± 11.2 | 72.5 ± 5.4 |
| Men | 74 (54) | 60 (51) | 14 (67) |
| LVEF (%) | 46.8 ± 8.1 | 48.0 ± 7.8 | 39.7 ± 5.4 |
| Diagnosis | |||
| Ischaemic heart disease | 60 (43) | 48 (41) | 12 (57) |
| DCMP | 78 (57) | 69 (59) | 9 (43) |
| History of hypertension | 81 (59) | 68 (58) | 13 (62) |
| Diabetes mellitus | 33 (24) | 30 (26) | 3 (14) |
| Atrial fibrillation | 68 (49) | 54 (46) | 14 (67) |
| Laboratory results | |||
| Creatinine (μmol/L) | 82.0 ± 37.1 | 77.5 ± 29.2 | 109.3 ± 61.7 |
| Uric acid (μmol/L) | 352.9 ± 115.6 | 336.1 ± 99.9 | 461.6 ± 137.8 |
| Total cholesterol (mmol/L) | 4.8 ± 1.1 | 4.9 ± 1.1 | 4.5 ± 1.2 |
| Triglycerides (mmol/L) | 1.6 ± 1.0 | 1.6 ± 1.0 | 1.2 ± 0.7 |
| HDL (mmol/L) | 1.2 ± 0.3 | 1.2 ± 0.3 | 1.1 ± 0.3 |
| LDL (mmol/L) | 2.9 ± 0.9 | 2.9 ± 0.9 | 2.6 ± 0.9 |
| Total bilirubin (μmol/L) | 18.2 ± 9.9 | 17.2 ± 8.6 | 23.9 ± 14.1 |
| BNP (pg/mL) | 316 ± 153 | 266 ± 79 | 592 ± 174 |
| Homocysteine (mg/L) | 16.5 ± 9.3 | 14.4 ± 6.3 | 28.6 ± 13.4 |
| hs-CRP (μmol/L) | 8.4 ± 9.8 | 6.4 ± 7.7 | 17.5 ± 14.1 |
| Cystatin C (mg/L) | 1.03 ± 0.47 | 0.91 ± 0.27 | 1.63 ± 0.81 |
| Pharmacotherapy | |||
| ACE inhibitor or ARB | 76 (55) | 62 (53) | 14 (67) |
| β-blocker | 80 (58) | 67 (57) | 13 (62) |
| Digitalis | 70 (51) | 57 (49) | 13 (62) |
| Diuretic | 78 (57) | 64 (55) | 14 (67) |
| Statin | 68 (49) | 56 (48) | 12 (57) |
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