Abstract
Cystatin C, which is an endogenous marker for renal function, has been reported to be associated with outcomes and risk stratification of coronary vascular disease patients. In this study, the relationship between the serum cystatin C level and characteristics of coronary plaques is evaluated in patients with coronary artery disease. The study involved 137 lesions in 82 patients. Plaque vulnerability, rupture, fibrotic cap thickness, microchannel, and calcified nodules were evaluated by optical coherence tomography. Cystatin C levels in acute coronary syndrome (ACS) patients and in non-ACS patients were 1.160 ± 0.595 and 0.973 ± 0.158 mg/L, respectively (P = 0.046). The cystatin C levels were not different between patients with and without ruptured plaques (P = 0.396), or between stable and unstable lesions (P = 0.223). There was correlation between cystatin C and calcified nodule in plaque (r = 0.188, P = 0.032). A significant negative correlation exists between the cystatin C levels and fibrous cap tissue thickness (r = −0.242, P = 0.018). Prior statin usage, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and cystatin C were independent contributors to fibrous cap thickness (P-value was 0.001, 0.001, 0.026, and 0.037, respectively). Cystatin C is not related with plaque rupture or stability, but it related with some plaque morphology, such as thin fibrous cap thickness and calcified nodule.
Introduction
Cystatin C, which is an endogenous marker for renal function, is reported to be a novel marker for coronary atherosclerosis.1 The concentration of cystatin C is strongly associated with long-term all-cause and cardiovascular mortality in patients referred to coronary angiography, irrespective of creatinine-based renal function.2 While it is not been reported that if the cystatin C level is related with the plaque vulnerability, autopsy studies have shown that the main components of vulnerable plaque are generally considered to be a lipid-rich plaque, a thin fibrous cap, microchannel structure, and spotty calcification. Intracoronary optical coherence tomography (OCT) is a powerful imaging technology for obtaining high-resolution cross-sectional images of tissue structure on the micron scale, in situ and in real time, and enables the detailed assessment of coronary plaque morphology. In this study, we evaluated the plaque morphology with OCT in coronary artery disease (CAD) patients, measured the serum cystatin C level, and evaluated the relationship between them.
Methods
Study population and laboratory test
From a total of 191 patients who were enrolled in the OCT database at Chinese PLA General Hospital between July 2012 and October 2014, we retrospectively screened 82 patients. The inclusion criteria for this study were: (i) coronary angiogram performed for CAD, (ii) the presence of lesions with ≥30 and <100% diameter stenosis, (iii) measured cystatin C level before angiogram and OCT examination, and (iv) adequate and distinct OCT images. The exclusion criteria included were (i) left ventricular wall motion abnormality on echocardiography, (ii) left main lesion, (iii) patients with acute ST-segment elevation myocardial infarction (STEMI), (iv) patients with acute heart failure, and (v) patients with renal failure. Acute STEMI was defined as continuous (>30 min) chest pain at rest with elevated level of troponin T (TnT; >0.1 mg/mL), and ST-segment elevation of at least 0.1 mV in two or more continuous electrocardiographic leads. Non-ST-segment elevation acute coronary syndrome (NSTE-ACS) included non-STEMI and unstable angina (UA). The criteria for NSTEMI in this study were new findings of ST-segment depression >1 mm or T-wave inversion >4 mm in two or more contiguous leads, symptoms consistent with acute MI, and elevated level of TnT (>0.1 mg/mL). Unstable angina was defined as an unstable pattern of chest pain (at rest, new onset, or crescendo angina) coinciding with objective evidence on coronary angiography, but without significant elevation in TnT (>0.1 mg/mL). The following classical coronary risk factors were assessed: age, gender, hypertension, diabetes mellitus, dyslipidaemia [serum total cholesterol (TC) level ≥220 mg/dL], current smoking, and family history.
Blood sample was collected on the early morning of the next day after admission. The cystatin C level was measured with a latex immunoturbidimetry assay on a Hitachi 7600 automated analyser (Hitachi Instruments Engineering), and the unit of measurement for the cystatin C was milligrams per litre. Total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and creatinine were measured using enzymatic methods with standard biochemical procedures on a B.M. Hitachi automated clinical chemistry analyser (Hitachi Instruments Engineering).
The study protocol was approved by the Chinese PLA General Ethics Committee, and all patients provided informed consent before participation.
Optical coherence tomography procedure and optical coherence tomography analysis
Optical coherence tomography examinations were performed after intracoronary administration of 200 µg nitroglycerin. Optical coherence tomography images were obtained using the LightLab C7-XR frequency domain OCT system (LightLab Imaging, Inc., Westford, MA, USA) with the non-occlusive technique. The imaging catheter was inserted through a 0.014-inch angioplasty wire to the distal end of the target lesion. Contrast then was infused (at a flow rate of 3–4 mL/s) from the tip of the guiding catheter to flush blood from the imaging field. At the same time, a motorized pullback system was used at 20 mm/s and OCT images were acquired at 100 frames/s. During this procedure, ST-segment elevation, patient symptoms, and haemodynamic conditions were observed carefully. Identification of two separate plaques in the same vessel required a ≥5 mm reference segment between them; if not, they were considered one long lesion. Plaque rupture, plaque erosion, calcified nodules, microchannel structure, thrombus, and thin-cap fibroatheroma (TCFA) were analysed (Figure 1). The cap thickness was measured frame by frame to determine the thinnest site. Plaque stability was determined. Optical coherence tomography images were analysed using the software from LightLab Imaging, Inc. by two independent observers who were blinded to the clinical situation. When there was any discordance between the observers, a consensus reading was obtained.
Representative cases of (1) thin-cap fibroatheroma, (2) microchannel, (3) plaque rupture, (4) plaque erosion, and (5) calcified nodule. (1) Lipid-rich plaque with lipid content in ≥1 quadrant and a thin fibrous cap of <65 μm. (2) Black hole with a diameter of 50–300 μm within a plaque. (3) Fibrous cap was broken at the mid-portion, a clear cavity formation inside the plaque. (4) Presence of attached thrombus overlying irregular plaque surface. (5) Calcification within an arc of <90°, calcium deposit showing a sharply delineated region with a signal-poor interior.
The related definitions were as follows: (i) calcified nodule: calcification within an arc of <90°. Calcification was defined as well-delineated, low back-scattering heterogeneous regions. Superficial calcified nodule was defined as calcified nodule with a thin fibrous cap of <100 μm; (ii) microchannel structure: a black hole with a diameter of 50–300 μm within a plaque that was present on at least three consecutive frames; (iii) thrombus: well-delineated, irregular mass protruded into the vessel lumen from the vessel wall with signal attenuation; (iv) plaque rupture: fibrous cap discontinuity with a clear cavity formation inside the plaque; (v) TCFA: plaque with lipid content in ≥1 quadrant and a thin fibrous cap of <65 μm. Lipid was defined as a diffusely bordered lesion that exhibits a lower signal density with high attenuation. The fibrous cap was measured as the signal-rich layer from the coronary artery lumen to the inner border of the underlying lipid; (vi) fibrous cap: was identified as a tissue layer that is a signal-rich homogeneous region overlying a lipid core characterized by a diffusely bordered, signal-poor region on the OCT image; (vii) plaque erosion: presence of attached thrombus overlying irregular plaque surface; (viii) unstable plaque: ruptured plaque, TCFA plaque, plaque with erosion, or superficial calcified nodules.
Angiographic analysis
Coronary angiograms were obtained at baseline; two identical orthogonal views were obtained after intracoronary nitrate treatment and stored on digital disc. Quantitative coronary angiographic analysis was performed using a computer-assisted, automated edge-detection algorithm by two independent observers who were blinded to clinical and OCT information. End-diastolic frames were chosen for quantitative analysis. The reference diameter, lesion length, diameter stenosis, and thrombolysis in MI flow were measured. The average diameter of normal segments proximal and distal to the treated lesion was used as the reference diameter.
Statistical analysis
All statistical analyses were performed by an independent statistician at the Core Laboratory with the Statistical Package for Social Sciences (SPSS) for Windows, version 19. Continuous variables were expressed as mean ± standard deviation and compared with t-test for normally distributed variables. Normal distribution were tested with the one-sample Kolmogorov–Smirnov test. Categorical variables were expressed as number and percentage, and compared using χ2 statistics or Fisher's exact test (if the expected cell value was <5). Correlations between variables were assessed using Spearman's or Pearson's bivariate correlation analysis. Multivariate linear regression was used to identify the contributors for cystatin C and fibrous cap thickness. A value of P< 0.05 was considered as statistically significant, and all P-values were two-sided.
Results
Baseline demographics and contributing factors to cystatin C level
We studied 82 patients (56 NSTE-ACS patients and 26 non-ACS patients). Clinical characteristics were summarized in Table 1. The cystatin C levels in ACS (UA or NSTEMI) patients had an intendancy to increase comparing with non-ACS patients (1.160 ± 0.595 vs. 0.973 ± 0.158 mg/L, respectively, P = 0.046, Figure 2). On bivariate correlation analysis, age, gender, hypertension, prior statin usage, haemoglobin, haematocrit, creatinine, TC, triglyceride, apoprotein (Apo) A1, Apo B, and lipoprotein (α) [LP(α)] were correlated with cystatin C (Table 2). On multivariate regression analysis, only age, creatinine, Apo B, and LP(α) were independent contributors (P-value was <0.001, <0.001, 0.001, and 0.004, respectively).
Baseline clinical and angiographic characteristics
| Variables | Value | Variables | Value |
|---|---|---|---|
| Male, n (%) | 73 (89.02) | Average age (year) | 47.23 ± 13.79 |
| ACS, n (%) | 56 (68.29) | Hypertension, n (%) | 42 (51.22) |
| Hypercholesterol, n (%) | 23 (28.05) | Diabetes, n (%) | 19 (23.17) |
| Smoking, n (%) | 43 (52.44) | Family history, n (%) | 12 (14.63) |
| Prior PCI, n (%) | 15 (18.29) | Lesion number, n | 137 |
| Lesion length (mm) | 23.30 ± 12.98 | Lesions location | – |
| Reference diameter (mm) | 3.11 ± 0.94 | LAD, n (%) | 69 (50.36) |
| Diameter stenosis (mm2) | 69.35 ± 18.28 | LCX, n (%) | 36 (26.28) |
| TIMI flow 3 grade, n (%) | 82 (100) | RCA, n (%) | 32 (23.36) |
| Variables | Value | Variables | Value |
|---|---|---|---|
| Male, n (%) | 73 (89.02) | Average age (year) | 47.23 ± 13.79 |
| ACS, n (%) | 56 (68.29) | Hypertension, n (%) | 42 (51.22) |
| Hypercholesterol, n (%) | 23 (28.05) | Diabetes, n (%) | 19 (23.17) |
| Smoking, n (%) | 43 (52.44) | Family history, n (%) | 12 (14.63) |
| Prior PCI, n (%) | 15 (18.29) | Lesion number, n | 137 |
| Lesion length (mm) | 23.30 ± 12.98 | Lesions location | – |
| Reference diameter (mm) | 3.11 ± 0.94 | LAD, n (%) | 69 (50.36) |
| Diameter stenosis (mm2) | 69.35 ± 18.28 | LCX, n (%) | 36 (26.28) |
| TIMI flow 3 grade, n (%) | 82 (100) | RCA, n (%) | 32 (23.36) |
ACS, acute coronary syndrome(s); LAD, left anterior descending artery; LCX, left circumflex artery; PCI, percutaneous coronary intervention; RCA, right coronary artery; TIMI, thrombolysis in myocardial infarction.
Baseline clinical and angiographic characteristics
| Variables | Value | Variables | Value |
|---|---|---|---|
| Male, n (%) | 73 (89.02) | Average age (year) | 47.23 ± 13.79 |
| ACS, n (%) | 56 (68.29) | Hypertension, n (%) | 42 (51.22) |
| Hypercholesterol, n (%) | 23 (28.05) | Diabetes, n (%) | 19 (23.17) |
| Smoking, n (%) | 43 (52.44) | Family history, n (%) | 12 (14.63) |
| Prior PCI, n (%) | 15 (18.29) | Lesion number, n | 137 |
| Lesion length (mm) | 23.30 ± 12.98 | Lesions location | – |
| Reference diameter (mm) | 3.11 ± 0.94 | LAD, n (%) | 69 (50.36) |
| Diameter stenosis (mm2) | 69.35 ± 18.28 | LCX, n (%) | 36 (26.28) |
| TIMI flow 3 grade, n (%) | 82 (100) | RCA, n (%) | 32 (23.36) |
| Variables | Value | Variables | Value |
|---|---|---|---|
| Male, n (%) | 73 (89.02) | Average age (year) | 47.23 ± 13.79 |
| ACS, n (%) | 56 (68.29) | Hypertension, n (%) | 42 (51.22) |
| Hypercholesterol, n (%) | 23 (28.05) | Diabetes, n (%) | 19 (23.17) |
| Smoking, n (%) | 43 (52.44) | Family history, n (%) | 12 (14.63) |
| Prior PCI, n (%) | 15 (18.29) | Lesion number, n | 137 |
| Lesion length (mm) | 23.30 ± 12.98 | Lesions location | – |
| Reference diameter (mm) | 3.11 ± 0.94 | LAD, n (%) | 69 (50.36) |
| Diameter stenosis (mm2) | 69.35 ± 18.28 | LCX, n (%) | 36 (26.28) |
| TIMI flow 3 grade, n (%) | 82 (100) | RCA, n (%) | 32 (23.36) |
ACS, acute coronary syndrome(s); LAD, left anterior descending artery; LCX, left circumflex artery; PCI, percutaneous coronary intervention; RCA, right coronary artery; TIMI, thrombolysis in myocardial infarction.
The correlation of serum cystatin C level and other clinical and biochemical variables
| Variables | Correlation coefficient | P-value |
|---|---|---|
| Age | 0.418 | <0.001* |
| Gender | 0.284 | 0.001* |
| Hypertension | 0.174 | 0.047* |
| Diabetes mellitus | 0.031 | 0.726 |
| Smoking | −0.156 | 0.076 |
| Family history | −0.006 | 0.946 |
| Prior statin usage | −0.297 | 0.001* |
| WBC | 0.118 | 0.188 |
| Neutrophil granulocyte | 0.071 | 0.430 |
| Haemoglobin | −0.247 | 0.005* |
| HCT | −0.308 | 0.001* |
| CRP | 0.104 | 0.295 |
| Glucose | 0.082 | 0.356 |
| Creatinine | 0.478 | <0.001* |
| TC | 0.179 | 0.044* |
| Triglyceride | 0.249 | 0.005* |
| Apo A1 | −0.349 | 0.001* |
| Apo B | 0.314 | 0.004* |
| LDL-C | 0.167 | 0.061 |
| HDL-C | −0.136 | 0.126 |
| LP(α) | 0.487 | <0.001* |
| Variables | Correlation coefficient | P-value |
|---|---|---|
| Age | 0.418 | <0.001* |
| Gender | 0.284 | 0.001* |
| Hypertension | 0.174 | 0.047* |
| Diabetes mellitus | 0.031 | 0.726 |
| Smoking | −0.156 | 0.076 |
| Family history | −0.006 | 0.946 |
| Prior statin usage | −0.297 | 0.001* |
| WBC | 0.118 | 0.188 |
| Neutrophil granulocyte | 0.071 | 0.430 |
| Haemoglobin | −0.247 | 0.005* |
| HCT | −0.308 | 0.001* |
| CRP | 0.104 | 0.295 |
| Glucose | 0.082 | 0.356 |
| Creatinine | 0.478 | <0.001* |
| TC | 0.179 | 0.044* |
| Triglyceride | 0.249 | 0.005* |
| Apo A1 | −0.349 | 0.001* |
| Apo B | 0.314 | 0.004* |
| LDL-C | 0.167 | 0.061 |
| HDL-C | −0.136 | 0.126 |
| LP(α) | 0.487 | <0.001* |
Apo, apoprotein; CRP, C-reactive protein; HCT, haematocrit; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LP, lipoprotein; TC, total cholesterol; WBC, white blood cell.
*P-value of <0.05.
The correlation of serum cystatin C level and other clinical and biochemical variables
| Variables | Correlation coefficient | P-value |
|---|---|---|
| Age | 0.418 | <0.001* |
| Gender | 0.284 | 0.001* |
| Hypertension | 0.174 | 0.047* |
| Diabetes mellitus | 0.031 | 0.726 |
| Smoking | −0.156 | 0.076 |
| Family history | −0.006 | 0.946 |
| Prior statin usage | −0.297 | 0.001* |
| WBC | 0.118 | 0.188 |
| Neutrophil granulocyte | 0.071 | 0.430 |
| Haemoglobin | −0.247 | 0.005* |
| HCT | −0.308 | 0.001* |
| CRP | 0.104 | 0.295 |
| Glucose | 0.082 | 0.356 |
| Creatinine | 0.478 | <0.001* |
| TC | 0.179 | 0.044* |
| Triglyceride | 0.249 | 0.005* |
| Apo A1 | −0.349 | 0.001* |
| Apo B | 0.314 | 0.004* |
| LDL-C | 0.167 | 0.061 |
| HDL-C | −0.136 | 0.126 |
| LP(α) | 0.487 | <0.001* |
| Variables | Correlation coefficient | P-value |
|---|---|---|
| Age | 0.418 | <0.001* |
| Gender | 0.284 | 0.001* |
| Hypertension | 0.174 | 0.047* |
| Diabetes mellitus | 0.031 | 0.726 |
| Smoking | −0.156 | 0.076 |
| Family history | −0.006 | 0.946 |
| Prior statin usage | −0.297 | 0.001* |
| WBC | 0.118 | 0.188 |
| Neutrophil granulocyte | 0.071 | 0.430 |
| Haemoglobin | −0.247 | 0.005* |
| HCT | −0.308 | 0.001* |
| CRP | 0.104 | 0.295 |
| Glucose | 0.082 | 0.356 |
| Creatinine | 0.478 | <0.001* |
| TC | 0.179 | 0.044* |
| Triglyceride | 0.249 | 0.005* |
| Apo A1 | −0.349 | 0.001* |
| Apo B | 0.314 | 0.004* |
| LDL-C | 0.167 | 0.061 |
| HDL-C | −0.136 | 0.126 |
| LP(α) | 0.487 | <0.001* |
Apo, apoprotein; CRP, C-reactive protein; HCT, haematocrit; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LP, lipoprotein; TC, total cholesterol; WBC, white blood cell.
*P-value of <0.05.
Cystatin C level in different situation. (1) Cystatin C level in acute coronary syndrome and non-acute coronary syndrome patients. (2) Cystatin C level and lesion location. (3) Cystatin C level in rupture and no rupture lesion group. (4) Cystatin C level in stable and unstable lesion groups.
Cystatin C level and angiographic or optical coherence tomography findings
A total of 137 lesions from 82 patients were analysed (85 lesions from NSTE-ACS patients and 52 lesions from non-ACS patients). Angiographic analyses are given in Table 1. Cystatin C levels were not associated with the lesion location (P = 0.499, Figure 2). Optical coherence tomography analysis showed that 23 (16.8%) lesions were ruptured, and another 19 (13.9%) lesions showed plaque erosion. The cystatin C levels were not different between patients with and without ruptured lesions (P = 0.396), or between patients with stable and unstable lesions (P = 0.223, Figure 2). A significant negative correlation exists between the cystatin C level and fibrous cap tissue thickness (r = −0.242, P = 0.018). The relationship between cystatin C and lesion location, microchannel in plaque, and calcified nodule in plaque was also analysed (correlation coefficient −0.130, −0.001, and 0.188; P-value 0.140, 0.992, and 0.032, respectively). Calcified nodule in plaque was mildly correlated with cystatin C.
Contributing factors to fibrous cap thickness
On bivariate correlation analysis, age, prior statin usage, white blood cell, creatinine, TC, triglyceride, Apo B, LDL-C, HDL-C, and cystatin C were correlated with plaque fibrous cap thickness (Table 3). On multivariate regression analysis, prior statin usage, LDL-C, HDL-C, and cystatin C were independent contributors to fibrous cap thickness (P-value was 0.001, 0.001, 0.026, and 0.037, respectively).
The correlation of fibrous cap thickness of plaque and clinical or biochemical variables
| Variables | Correlation coefficient | P-value |
|---|---|---|
| Age | −0.228 | 0.026* |
| Gender | −0.200 | 0.052 |
| Hypertension | −0.106 | 0.307 |
| Diabetes mellitus | 0.190 | 0.065 |
| Smoking | 0.015 | 0.885 |
| Family history | −0.080 | 0.440 |
| Prior statin usage | 0.316 | 0.002* |
| WBC | −0.285 | 0.006* |
| Neutrophil granulocyte | −0.048 | 0.651 |
| Haemoglobin | 0.057 | 0.592 |
| HCT | 0.162 | 0.142 |
| CRP | −0.150 | 0.185 |
| Glucose | 0.067 | 0.521 |
| Creatinine | −0.287 | 0.005* |
| TC | −0.276 | 0.008* |
| Triglyceride | −0.295 | 0.004* |
| Apo A1 | 0.093 | 0.458 |
| Apo B | −0.391 | 0.001* |
| LDL-C | −0.252 | 0.016* |
| HDL-C | 0.051 | 0.028* |
| LP(α) | −0.180 | 0.156 |
| Cystatin C | −0.508 | 0.000* |
| Variables | Correlation coefficient | P-value |
|---|---|---|
| Age | −0.228 | 0.026* |
| Gender | −0.200 | 0.052 |
| Hypertension | −0.106 | 0.307 |
| Diabetes mellitus | 0.190 | 0.065 |
| Smoking | 0.015 | 0.885 |
| Family history | −0.080 | 0.440 |
| Prior statin usage | 0.316 | 0.002* |
| WBC | −0.285 | 0.006* |
| Neutrophil granulocyte | −0.048 | 0.651 |
| Haemoglobin | 0.057 | 0.592 |
| HCT | 0.162 | 0.142 |
| CRP | −0.150 | 0.185 |
| Glucose | 0.067 | 0.521 |
| Creatinine | −0.287 | 0.005* |
| TC | −0.276 | 0.008* |
| Triglyceride | −0.295 | 0.004* |
| Apo A1 | 0.093 | 0.458 |
| Apo B | −0.391 | 0.001* |
| LDL-C | −0.252 | 0.016* |
| HDL-C | 0.051 | 0.028* |
| LP(α) | −0.180 | 0.156 |
| Cystatin C | −0.508 | 0.000* |
Apo, apoprotein; CRP, C-reactive protein; HCT, haematocrit; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LP, lipoprotein; TC, total cholesterol; WBC, white blood cell.
*P-value of <0.05.
The correlation of fibrous cap thickness of plaque and clinical or biochemical variables
| Variables | Correlation coefficient | P-value |
|---|---|---|
| Age | −0.228 | 0.026* |
| Gender | −0.200 | 0.052 |
| Hypertension | −0.106 | 0.307 |
| Diabetes mellitus | 0.190 | 0.065 |
| Smoking | 0.015 | 0.885 |
| Family history | −0.080 | 0.440 |
| Prior statin usage | 0.316 | 0.002* |
| WBC | −0.285 | 0.006* |
| Neutrophil granulocyte | −0.048 | 0.651 |
| Haemoglobin | 0.057 | 0.592 |
| HCT | 0.162 | 0.142 |
| CRP | −0.150 | 0.185 |
| Glucose | 0.067 | 0.521 |
| Creatinine | −0.287 | 0.005* |
| TC | −0.276 | 0.008* |
| Triglyceride | −0.295 | 0.004* |
| Apo A1 | 0.093 | 0.458 |
| Apo B | −0.391 | 0.001* |
| LDL-C | −0.252 | 0.016* |
| HDL-C | 0.051 | 0.028* |
| LP(α) | −0.180 | 0.156 |
| Cystatin C | −0.508 | 0.000* |
| Variables | Correlation coefficient | P-value |
|---|---|---|
| Age | −0.228 | 0.026* |
| Gender | −0.200 | 0.052 |
| Hypertension | −0.106 | 0.307 |
| Diabetes mellitus | 0.190 | 0.065 |
| Smoking | 0.015 | 0.885 |
| Family history | −0.080 | 0.440 |
| Prior statin usage | 0.316 | 0.002* |
| WBC | −0.285 | 0.006* |
| Neutrophil granulocyte | −0.048 | 0.651 |
| Haemoglobin | 0.057 | 0.592 |
| HCT | 0.162 | 0.142 |
| CRP | −0.150 | 0.185 |
| Glucose | 0.067 | 0.521 |
| Creatinine | −0.287 | 0.005* |
| TC | −0.276 | 0.008* |
| Triglyceride | −0.295 | 0.004* |
| Apo A1 | 0.093 | 0.458 |
| Apo B | −0.391 | 0.001* |
| LDL-C | −0.252 | 0.016* |
| HDL-C | 0.051 | 0.028* |
| LP(α) | −0.180 | 0.156 |
| Cystatin C | −0.508 | 0.000* |
Apo, apoprotein; CRP, C-reactive protein; HCT, haematocrit; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LP, lipoprotein; TC, total cholesterol; WBC, white blood cell.
*P-value of <0.05.
Discussion
This study has shown that cystatin C level is associated with some plaque morphology, such as thin fibrous cap thickness and calcified nodule, but no relationship with plaque stability.
Cystatin C and related factors
Cystatin C is a small protein molecule (120 amino acid peptide chain, ∼13 kDa) produced by nearly all nucleated cells in the human body. Plasma cystatin C is a marker for chronic kidney disease. In the present study, cystatin C is also significantly related with serum creatinine level. The analysis also shows that cystatin C levels have a tendency to increase with age (P < 0.001). Similar observations were made by Finney et al.3 and Kottgen et al.4 Moreover, in the present study, cystatin C level is also significantly correlated with the LP(α) and Apo B, which means that there may exist some relationships between cystatin C and lipid metabolism, which need further studies.
Cystatin C and coronary artery disease
Although there are some conflicting reports, most studies showed that cystatin C was related with CAD.5–7 Batra et al.8 carried out a prospective study on 150 Indian patients undergoing coronary angiography. The authors found that higher plasma cystatin C levels were associated with higher carotid intimal medial thickness, diffuse CAD, and more frequent occurrence of triple vessel disease. Cystatin C was significantly higher in the UA group than in the stable angina group, and positively correlated with plaque area and plaque burden in the UA group but not in the stable angina group.9–13 In the present study, cystatin C levels in ACS (UA or NSTEMI) patients had an intendancy to increase comparing with non-ACS patients (P < 0.05). For OCT technique limitation, we had not evaluated the plaque volume. Cystatin C also could be used as a prognostic risk factor in patients with stable CAD.14 Negrusz-Kawecka et al.15 reported that elevated cystatin C levels increased the risk of ACS, especially the risk of STEMI. Jernberg et al.16 reported that, in patients with a suspected or confirmed ACS, a single measurement of cystatin C significantly improved the early stratification of risk. In another study, the cystatin C concentration independently predicted the risk of cardiovascular death in CAD.17,18
Currently, it is not quite clear whether cystatin C is a prognostic marker solely because it is a more sensitive indicator of renal function, or because it also reflects adverse pathological mechanisms that are partially or totally independent of renal function. And, numerous studies tried to explain it. For example, there is evidence that inflammatory status, thyroid disease, serum C-reactive protein, and current smoking were all associated with cystatin C concentrations.6,19 This may explain in part the mechanism underlying the statistical link between cystatin C and cardiovascular outcomes in subjects with normal creatinine-based glomerular filtration rate. The finding that cystatin C and CAD partly share common genes may also indicate a possible causal relation between cystatin C and CAD.20 In the present study, cystatin C levels are also significantly correlated with the LP(α) and Apo B, which means atherosclerosis may be induced by cystatin C through altering lipid metabolism, which need further studies.
Cystatin C and plaque morphology
From the pathological studies, we know that thrombosis following plaque erosion or plaque rupture is the basic aetiology of ACS. Elastolytic cysteine proteases and their inhibitors, including cystatin C, are believed to be involved in the pathogenesis of atherosclerosis.21 However, until now, there were no reports about cystatin C and plaque morphology. Optical coherence tomography could be used to evaluate plaque morphology in vivo for its high resolution. In the present study, cystatin C is related with the fibrous cap thickness and calcified nodule in plaque, while it is not related with microchannel in plaque, plaque rupture, and unstable plaque. In the present study, except cystatin C, the LDL-C, HDL-C, and prior statin usage are also related with fibrous cap thickness. Similarly, Ozaki et al.22 have investigated the relationship between lesion vulnerability and HDL-C levels, and they showed that the fibrous cap thickness was related with the low HDL-C level, high LDL-C level, high-sensitivity C-reactive protein level, and current smoking. Unfortunately, we failed to clarify the reasons for the plaque morphology changes given by cystatin C, but it is likely to be related to the sensitivity of cystatin C to detect preclinical kidney dysfunction, inflammation, lipid metabolism, or others. Mice that are doubly deficient in cystatin C and apolipoprotein E have consistently increased collagen contents and better developed fibrous caps.23 This suggests that cystatin C expression may induce degradation of the collagen forming cathepsins, and may be related with plaque morphology changes.
Study limitations
We did not perform a three-vessel assessment; therefore, it is possible that some patients might have a vulnerable plaque in another coronary artery. The OCT definition of plaque erosion and unstable plaque was different from the pathological definition, and this may affect the result. The limited penetration depth of OCT does not allow for evaluation of plaque volume; therefore, it is difficult to estimate and quantify the amount of lipids on OCT. The present study consists of patients with two different conditions: ACS and non-ACS. The physiopathology is much less uniform, ranging from an acute unstable situation to a chronic coronary pathology. The single-centre retrospective design of this study and the very small sample size undermine evaluation. A study involving larger patient populations from various centres is warranted.
Conclusion
Cystatin C is independently correlated with fibrous cap thickness of plaque in patients with CAD, as well as HDL-C, LDL-C, and prior statin usage. Cystatin C is also correlated with the calcified nodule in plaque, but not with microchannel in plaque or plaque rupture. This suggests that various mechanisms are involved in provoking unstable plaque.
Conflict of interest: Pharmaceutical or medical device companies had no input into the design of the study or in the preparation of the paper. All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
