Abstract
Aims: ST-segment elevation myocardial infarction (STEMI) is an acute inflammatory and thrombotic disease due to coronary artery atherosclerotic lesions. Studies have established the correlation of serum sulfatides with inflammation, thrombogenesis, and atherosclerosis. We observed that serum sulfatides level significantly increased in STEMI patients. In this study, we try to identify the relationship of serum sulfatides level on clinical outcomes of patients in STEMI.
Methods: Serum sulfatides level was monitored in 370 inpatients within 24 h of STEMI onset. On the basis of the level of serum sulfatides that was below 10 µmol/L in the normal population, the patients were divided into two groups with the median value of 15.2 µmol/L; low sulfatide group [serum sulfatides level ≤ 15.2 µmol/L (n = 200)] and high sulfatide group [serum sulfatides level > 15.2 µmol/L (n = 170)]. Patients' baseline characteristics, in-hospital outcomes, and late major adverse cardiovascular events (MACE) were analyzed. Independent incident for in-hospital death and late adverse events were modeled by multivariate logistic and Cox regression analysis.
Results: Between the two groups, there were no differences in the angiographic characteristics, percutaneous coronary intervention (PCI) results, and in-hospital recovery. However, high serum sulfatides level is positively correlated with increased rate of in-hospital death (OR 0.971; 95% CI 0.926–0.990, p = 0.019). In addition, this group of patients has more cumulative incidences of target vessel revascularization (TVR) (23% vs. 8%, p < 0.05) and increased overall MACE (28% vs. 10%, p < 0.05). Cox regression analysis indicated that high serum sulfatides level contributes to TVR and overall MACE.
Conclusions: Elevated serum sulfatides level positively correlate with in-hospital death and complications (TVR and MACE) in STEMI patients.
Keywords: Serum sulfatide, Myocardial infarction, Coronary, Revascularization, Outcome
Introduction
It has been known for decades that ST-segment elevation myocardial infarction (STEMI) is a process of acute inflammatory and thrombotic formation inside the coronary artery, which causes immediate clinical suffering and manifests in short- and longterm complications, such as acute pumping failure, fatal arrhythmia, myocardial rupture, and chronic left ventricular dysfunction1, 2). Even with immediate percutaneous coronary revascularization (PCI), a large number of patients remain at risk for early electrical/mechanical complications and subsequent major adverse cardiac events (MACE) from myocardial stunning, adverse left ventricular remodeling, culprit lesion restenosis, and de novo coronary stenosis3). Early detection and diagnosis are the keys to preventing the progression of STEMI and improving patients' prognosis and the hospital survival rate4, 5). Currently, traditional methods, including an early electrocardiogram, coronary angiography, and a panel of enzymatic analyses are applied in the diagnosis of acute myocardial infarction, but there is still a lack of efficient early detection of STEMI6, 7). Actually, some biomarkers were identified and may be involved in the process of plaque formation to STEMI. However, their sensitivity and specificity still need to be examined8, 9). Therefore, a novel biomarker is urgently needed for the effective diagnosis and treatment of STEMI.
Sulfatide is a kind of ester, which with sulfuric acid and galactosylceramides at C3 of the galactosyl residue, presents in mammalian serum as a major component of glycosphingolipids in lipoproteins10). Vast experimental and clinical studies have revealed that serum sulfatides are strongly connected to an inflammatory reaction and thrombogenesis and even the buildup of the extracellular matrix in a damaged vessel11–13). Given that serum sulfatides contribute to atherosclerosis11, 12) and coronary artery disease (CAD) and have been reported as a novel biomarker for CAD in patients with end-stage renal failure14), we explored the association of circulating sulfatides level with the outcomes of STEMI in 370 inpatients. Our results indicated that sulfatides might be a valuable biomarker for the early clinical diagnosis and the effective treatment of STEMI as well.
Methods
Participants
We analyzed the data from 370 inpatients (230 males, 140 females; mean age, 67.9 ± 10.3 years) at Hebei General Hospital with a diagnosis of STEMI from March 2009 to February 2013. The median (25th to 75th percentiles) level of serum sulfatides was 15.2 (10.8–21.9) µmol/L. The patients were divided into two groups based on their value (15.2 µmol/L) of serum sulfatides at admission: below the median (n = 200) or above the median (n = 170). The diagnosis of STEMI was made on the basis of standardized criteria2). All of the patients consented to have emergency coronary angiography to define the coronary anatomy.
Our study was performed in conformity with the Declaration of Helsinki. We acquired signed informed consent from every one of the participants, and the Medical Ethics Committee of Hebei General Hospital authorized the study procedures.
Quantitative Analysis of Serum Sulfatide
Once the patient was admitted, peripheral blood samples were collected in the cath lab and a panel of biochemistry factors, such as glucose, HbA1c, creatine kinase, and other biomarkers, were measured with standardized assays. An aliquot of serum was stored at −80°C for the measurement of sulfatide. In brief, sulfatide was extracted from the serum, and it was then analyzed as lyso-forms using our established method15). The total lipids, including sulfatides, were extracted from 50 µL of serum with n-hexane: isopropanol (3:2, v/v). After samples were dried, we continued to hydrolyze the dried samples with 0.1 N of NaOH in 90% methanol at 150°C for 30 min to convert sulfatide to lyso-sulfatide, followed by desalting with Mono-tip C18 tips (GL Sciences, Tokyo, Japan). Lastly, all of the specimens were examined with matrix-assisted laser desorption ionization time-of-flight mass spectrometry including delayed ion extraction employing a Voyager Elite XL (6.5 m flight length in the reflector mode) Biospectrometry Workstation (PerSeptive Biosystems, Framingham, MA, USA). A nitrogen laser (337 nm) was implemented for ionization and negative ion mode detection.
Clinical Assessment
Discharged patients were closely followed-up with phone interviews and outpatient clinics. The following data were collected: non-fatal myocardial infarction, target vessel revascularization (TVR), coronary artery bypass grafting, and cardiac-related death in overall mortality. Effects of the administration of lipid-lowering (e.g., statins) and non-lipid-lowering medicines (e.g., aspirin, β-blockers, clopidogrel, angiotensin receptor antagonists, angiotensin-converting enzyme inhibitors, and aldosterone receptor antagonist) were also compared between the groups.
Statistical Analysis
The data are expressed as mean ± standard deviation. Continuous variables were compared using Student's t test. Correlations between serum sulfatides and other continuous variables were examined by univariate analysis. The multivariate logistic regression model identified independent correlates of in-hospital mortality for every patient. Rationale variables chosen for regression analysis involved demographic characteristics, co-morbid illnesses, and angiographic features. Variables were assessed in a backward conditioned multivariate logistic regression model when their univariate p values were < 0.20. Statistical significance was established as multivariate p < 0.05. The odds ratios and their respective 95% confidence intervals (CIs) from the multivariate logistic regression analysis were employed as estimates of relative risk. Multivariate Cox proportional hazard analysis was applied to identify the independent predictors of TVR and MACE, after modifying for baseline and angiographic variables with unequal distribution. A p value < 0.05 was deemed to be significant for every one of the analyses. Data were statistically processed with SPSS software version 18.0 (SPSS, Chicago, IL, USA).
Results
High sulfatides decrease estimated glomerular filtration rate (eGFR) but increase serum glucose and peak creatine phosphokinase (CPK) in STEMI patients. The random STEMI patient data were divided into two groups according to their serum sulfatides level. As shown in Table 1, the clinical characteristics and medication history of the patients were comparable as indicated by the p values. However, in contrast to the lower sulfatides group, the higher serum sulfatides (above the median group) significantly reduced eGFR (p < 0.001) and increased serum glucose (p < 0.001) and peak CPK (p < 0.05) among all of the 14 biochemical factors that we tested. To further determine the relationship of the sulfatides level with the changes of the serum factors, linear regression analysis was performed. As shown in Table 2, a high sulfatides level was strongly correlated with decreased eGFR (r = −0.118, p = 0.043), increased glucose (r = 0.235, p = 0.001), and peak CPK (r = 0.311, p = 0.015), but not with other biomarkers, such as troponin T, BNP, and hs-CRP. These data suggested that increased sulfatides are may be involved in the process of STEMI.
Table 1. Baseline Characteristies of patients with ST-Segment Elevation Myocardial Infarction Stratified According to Median Level (l5.2 µmol/l) of Serum sufatide.
| Serum sufatide = 15.2 µmol/l | Serum sufatide > 15.2 µmol/l | P Value | |
|---|---|---|---|
| (n = 200) | (n = 170) | ||
| Clincical Characteristics | |||
| Age (years) | 69.1 ± 10.2 | 66.3 ± 10.5 | NS |
| Female (%) | 79 (39.5) | 61 (35.9) | NS |
| Hypertension (%) | 110 (55.0) | 98 (57.6) | NS |
| DM (%) | 98 (49.0) | 86 (50.6) | NS |
| Smoking (%) | 151 (75.5) | 123 (72.4) | NS |
| BMI (kg/m2) | 24.3 ± 2.3 | 25.1 ± 3.0 | NS |
| Previous CAD (%) | 33 (16.5) | 23 (13.5) | NS |
| Previous Stroke (%) | 19 (9.5) | 15 (8.8) | NS |
| Carotid Stenosis (%) | 6 (3.0) | 4 (2.4) | NS |
| PAD (%) | 5 (2.5) | 3 (1.8) | NS |
| LVEF(%) | 45 ± 11 | 43 ± 12 | NS |
| Biochemical Data | |||
| eGFR (ml/min) | 58.1 ± 19.9 | 45.9 ± 17.7 | < 0.001 |
| TC (mmol/l) | 5.2 ± 1.2 | 5.2 ± 1.2 | NS |
| TG (mmol/l) | 1.4 ± 0.8 | 1.3 ± 0.8 | NS |
| HDL-C (mmol/l) | 1.1 ± 0.3 | 1.0 ± 0.2 | NS |
| LDL-C (mmol/l) | 3.2 ± 1.0 | 3.2 ± 1.0 | NS |
| Glucose (mmol/l) | 7.3 ± 3.9 | 9.9 ± 4.5 | < 0.001 |
| HbA1c (%) | 6.2 ± 1.1 | 6.9 ± 1.2 | NS |
| BNP (pg/dl) | 58.7 ± 19.7 | 62.3 ± 21.2 | NS |
| hs-CRP (µg/dl) | 153 ± 87 | 201 ± 95 | NS |
| CPK (IU/L) | 216 ± 65 | 229 ± 78 | NS |
| CK-MB (IU/L) | 25 ± 17 | 28 ± 19 | NS |
| Troponin T (ng/ml) | 0.18 ± 0.09 | 0.24 ± 0.10 | NS |
| Peak CPK (IU/L) | 1990 ± 983 | 3760 ± 1230 | < 0.05 |
| Peak CK-MB (IU/L) | 175 ± 68 | 249 ± 79 | NS |
| Medication on Admission | |||
| Aspirin, n (%) | 30 (15) | 27 (16) | NS |
| Clopidogrel, n (%) | 4 (2) | 5 (3) | NS |
| ACEI or ARB, n (%) | 58 (29) | 53 (31) | NS |
| B-Blocker, n (%) | 20 (10) | 15 (9) | NS |
| Statin, n (%) | 34 (17) | 27 (16) | NS |
| Aldosterone receptor antagonist, n (%) | 4 (2) | 5 (3) | NS |
Data are presented as frequency (percentage) for categorical variables and as mean ± standard deviation or median (interquartile range) for continuous variables.
NS, not significant; CAD, coronary artery disease; DM, diabetes mellitus; PAD, peripheral arterial disease; LVEF, left ventricular ejection fraction; BMI, body mass index; BNP, B-type natriuretic peptide; CK-MB, creatine kinase myocardial isoform; CPK, creatine phosphokinase; eGFR, estimated glomerular filtration rate; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin Ⅱ receptor blocker.
Table 2. Spearman Correlation Coefficients (R) Between Serum Sulfatide Levels and Continuous Cariables in the Patients with STEMI.
| Spearman R | P Value | |
|---|---|---|
| Age (years) | −0.112 | 0.181 |
| BMI (kg/m2) | 0.022 | 0.843 |
| LVEF (%) | −0.087 | 0.323 |
| eGFR (ml/min) | −0.118 | 0.043 |
| Triglycerides (mmol/l) | 0.100 | 0.245 |
| LDL-C (mmol/l) | −0.028 | 0.801 |
| HDL-C (mmol/l) | −0.055 | 0.501 |
| Glucose (mmol/l) | 0.235 | 0.001 |
| HbA1c (%) | 0.072 | 0.365 |
| BNP (pg/dl) | 0.030 | 0.737 |
| hs-CRP (µg/dl) | 0.129 | 0.063 |
| CPK (IU/L) | 0.032 | 0.711 |
| CK-MB (IU/L) | −0.005 | 0.899 |
| Troponin T (ng/ml) | 0.038 | 0.675 |
| Peak CRP (IU/L) | 0.311 | 0.015 |
| Peak CK-MB (IU/L) | 0.157 | 0.068 |
STEMI, ST-segment elevation acute myocardial infarction. Other abbreviations as in Table 1.
High sulfatides did not affect coronary angiography, interventional treatment, and short-term recovery. As shown in Table 3, we also investigated the patients' other in-hospital clinical data, such as the culprit lesion vessel, the severity of overall CAD, the door-to-balloon time, initial TIMI flow, and the therapeutic modalities of PCI in terms of thrombectomy, balloon angioplasty, and endovascular stents. There were no differences between these two groups (p > 0.05). In-hospital complications, such as respiratory failure, cardiogenic shock, new atrial fibrillation, and the need for emergency coronary bypass surgery, were also statistically equivalent in these two groups (p > 0.05). Even though there were 10 in-hospital deaths in the group with the serum sulfatide levels above the median, and 8 patient deaths in the group with the serum sulfatides below the median, the t test was not statistically significant (p > 0.05). However, both univariate regression and multivariate regression analysis identified that the serum sulfatides level and the number of diseased coronary > 1 was positively related to in-hospital death for all of these patients (Table 4).
Table 3. Coronary angiograpphic findings, PCI results and in hospital outcomes in all patients.
| Serum sufatide = 15.2 µmol/l | Serum sufatide > 15.2 µmol/l | P Value | |
|---|---|---|---|
| (n = 200) | (n = 170) | ||
| Angiographic Characteristics | |||
| No of diseased vessels | |||
| SVD, n (%) | 74 (37) | 70 (41) | NS |
| DVD, n (%) | 64 (32) | 49 (29) | NS |
| TVD, n (%) | 62 (31) | 51 (30) | NS |
| Treated (culprit) vessels | |||
| RCA, n (%) | 66 (33) | 63 (37) | NS |
| LMT, n (%) | 2 (1) | 1 (1) | NS |
| LAD, n (%) | 110 (55) | 85 (50) | NS |
| LCX, n (%) | 22 (11) | 13 (12) | NS |
| Initial TIMI flow | |||
| 0, n (%) | 134 (67) | 121 (71) | NS |
| 1,n (%) | 24 (12) | 14 (8) | NS |
| 2, n (%) | 12 (6) | 14 (8) | NS |
| 3, n (%) | 30 (15) | 21 (18) | NS |
| Door to balloon time (min) | 89.7 ± 28.5 | 90.1 ± 37.2 | NS |
| Interventions | |||
| Balloon angioplasty (%) | 194 (97) | 168 (99) | NS |
| Thrombectomy | |||
| Aspiration (%) | 134 (67) | 109 (64) | NS |
| Rheolytic (%) | 6 (3) | 5 (3) | NS |
| Stenting | |||
| Nil (%) | 24 (12) | 19 (11) | NS |
| DES (%) | 48 (24) | 42 (25) | NS |
| BMS (%) | 124 (62) | 102 (60) | NS |
| DES+BMS (%) | 4 (2) | 7 (4) | NS |
| In-hospital complications | |||
| New cardiogenic shock (%) | 24 (12) | 24 (14) | NS |
| Respiratory failure (%) | 38 (19) | 34 (20) | NS |
| Ventricular arrhythmia (%) | 30 (15) | 27 (16) | NS |
| New atrial fibrillation (%) | 16 (8) | 15 (9) | NS |
| Emergercy CABG (%) | 6 (3) | 3 (2) | NS |
| In-hospital Death (%) | 8 (4) | 10 (6) | NS |
SVD, single vessel disease; DVD, double-vessel disease; TVD, triple-vessel disease; RCA, right coronary artery; LMT, left main coronary artery; LAD, left anterior descending artery; LCX, left circumflex artery; TIMI, Thrombolysis in Myocardial Infarction; DES, drug-eluting stent; BMS, bare-metal stent; CABG, coronary artery bypass grafting.
Table 4. Independent predictors of in-hospital mortality in patients with STEMI undergoing PCI.
| Variable | Hazard ratio | 95%C.I. | P* | P+ |
|---|---|---|---|---|
| Variables in the model | ||||
| CAD number | 4.558 | 1.012–20.115 | 0.032 | 0.048 |
| 1 (reference) | 1 | |||
| > 1 | 4.558 | 1.012–20.115 | 0.032 | 0.048 |
| Serum sulfatide | 0.971 | 0.926–0.990 | 0.048 | 0.019 |
| Variables not in the model | ||||
| Door to balloon time | 0.699 | |||
| LM involvement | 0.107 | NS | ||
| Cardiogenic shock | 0.003 | NS | ||
| Culprit LAD | 0.301 | |||
| Culprit LCX | 0.852 | |||
| Culprit RCA | 0.437 | |||
| Culprit LM | 0.020 | NS | ||
| TIMI grade | < 0.001 | NS | ||
| Thrombectomy | ||||
| Aspiration | 0.341 | |||
| Rheolytic | 0.039 | NS |
From univariate regression analysis,
from multivariate regression analysis. CAD, coronary artery disease. Other abbreviations as in Table 3.
Long-term clinical outcomes. All of the patients discharged after STEMI were medicated under the same protocol. The Kaplan–Meier survival test showed that during a mean follow-up period of 1.6 years (1.63 ± 0.87 years), the patients with a serum sulfatides level above the median had more incidences of TVR at the rate of 23% versus 8% in the low sulfatides group (p < 0.05). Therefore, the overall MACE was significantly higher (28% vs. 10%, p < 0.05) in the high sulfatides group than it was in the low sulfatides group, but the rates of non-fatal myocardial infarction, novo lesions, cardiac deaths, and all causes of mortality were comparable between these two groups (Table 5). Then, we performed multivariate Cox regression analysis. After adjusting for gender, age, smoking, diabetes mellitus, left ventricular ejection fraction, peak CKP level, balloon angioplasty only, bare-metal stent, drug-eluting stent, all medications, triglyceride, serum total cholesterol, low-density lipoprotein (LDL) level, and high-density lipoprotein (HDL) level, we found that TVR and MACE are independent predictors of serum sulfatides. The hazard ratio for sulfatides of TVR was 0.997 (95% CI 0.991–0.999, p < 0.001), and overall MACE was 0.995 (95% CI 0.989–0.998, p < 0.001), respectively (Table 6).
Table 5. Medications at discharge and late clinical outcomes in patients with STEMI.
| Serum sufatide = 15.2 µmol/l | Serum sufatide > 15.2 µmol/l | P Value | |
|---|---|---|---|
| (n = 192) | (n = 160) | ||
| Medications at discharge | |||
| Aspirin, n (%) | 190 (99) | 160 (100) | NS |
| Clopidogrel, n (%) | 188 (98) | 158 (99) | NS |
| ACEI or ARB, n (%) | 182 (95) | 149 (93) | NS |
| B-Blocker, n (%) | 101 (53) | 98 (61) | NS |
| Statin, n (%) | 171 (89) | 141 (88) | NS |
| Aldosterone receptor artagoinst, n (%) | 61 (32) | 56 (35) | NS |
| MACE | |||
| Non-fatal MI, n (%) | 27 (14) | 26 (16) | NS |
| TVR, n (%) | 16 (8) | 37 (23) | < 0.05 |
| De novo lesion, n (%) | 29 (15) | 27 (17) | NS |
| Cardiac Death, n (%) | 0 (0) | 1 (1) | NS |
| All-Cause Mortality, n (%) | 23 (12) | 24 (15) | NS |
| Overall, n (%) | 19 (10) | 45 (28) | < 0.05 |
MACE, major adverse cardiovascular events; MI, myocardial infarction; TVR, target vessel revascularization. Other abbreviations as in Table 1.
Table 6. Independent predictors of TVR and overall MACE by multivariate Cox regression analysis in all patients.
| Variable | Hazard ratio | 95%C.I. | P Value |
|---|---|---|---|
| TVR | |||
| Serum Sulfatide | 0.997 | 0.991–0.999 | < 0.001 |
| CAD number | |||
| 1 (reference) | 1 | ||
| > 1 | 2.832 | 1.701–5.002 | < 0.001 |
| Overall MACE | |||
| Serum sulfatide | 0.995 | 0.989–0.998 | < 0.001 |
| CAD number | |||
| 1 (reference) | 1 | ||
| > 1 | 2.816 | 1. 729–4.621 | < 0.001 |
Other abbreviations as in Table 5.
Discussion
The present study showed that a higher level of serum sulfatides (> 15.2 µmol/L) in STEMI patients is an unfavorable correlate for in-hospital death as well as incidences of late TVR and overall MACE. It also suggested that the serum sulfatides level could be used as a marker for the severity of heart injury.
It is well known that STEMI is an acute block-age of the coronary artery in atherosclerotic lesions. Factors, such as high serum lipids, hypertension, and intimal damage of artery, contribute to the development of the disease. Even with the current technical advances in the early diagnosis and treatments, such as PCI, patients with STEMI remain at a high risk for death16) and many with poor prognoses, such as severe ventricular arrhythmia, cardiogenic shock, or cardiac rupture. Sulfatides are sphingoglycolipids found at the extracellular leaflet of the plasma membrane of most eukaryotic cells. They are expressed predominantly in the myelin sheath of the nervous system, but they are also found on the surface of blood cells and as a component of lipoproteins in blood serum12). Sulfatides exist in mammalian serum and are synthesized and secreted mainly from the liver as a component of lipoproteins13). In addition, they participate in a wide range of cellular processes, including cell adhesion and aggregation, neural plasticity, and immune responses. Importantly, our early study found that changes in cellular and serum circulating sulfatides directly impact cardiovascular diseases in patients with renal dysfunctions14). In cardiovascular diseases, sulfatides have tremendous physiological roles in the vascular inflammation linked with the initiation of atherothrombosis or atherosclerosis, particularly after vascular damage11). In events, such as atherosclerosis, angiography, and stent implantation, leukocytes, neutrophils, and monocytes interact with platelets through cell adhesion molecules17, 18). The sulfatides are recognized as native ligands of P-selectin and communicate with several cell adhesion molecules as well. Once neutrophil activation occurs after vascular injury, sulfatides will be released from the activated neutrophils. These sulfatides act agonistically as a P-selectin ligand, leading to P-selectin/Mac-1 cross talking and the activation of Mac-119–21). Studies have also demonstrated that sulfatides specifically bind to extracellular matrix components, such as thrombospondin, laminin, and von Willebrand factor19). The release of sulfatides from the surface of the neutrophils and in combination with an increased expression of P-selectin on the surface of platelets led to the accumulation of cytokines and the extracellular matrix in vessel lesions, resulting in increased vascular wall thickness20, 21).
Previous studies have also shown that sulfatides are involved in the progress of lipid metabolism in the development of atherosclerosis. In a study that implemented a rabbit model for human familial hypercholesterolemia-Watanabe heritable hyperlipidemic (WHHL), Hara and Taketomi showed that the heightened level of sulfatides in lipoprotein and atherosclerosis plaques is tightly correlated with the progression of atherosclerosis in WHHL rabbits. The serum sulfatides in the WHHL rabbit were notably multiplied 40-fold over the typical rabbit level. In addition, the lipid analysis of the atherosclerosis aorta of WHHL rabbits revealed a substantial buildup of sulfatides at the lesions, but not in the typical aorta12). All of these studies demonstrated that sulfatides are pathogenic factors for the initiation and progression of cardiovascular diseases.
It has been known that HDL-C and LDL-C levels decreased to below their baseline once patients have STEMI. But our study was designed to observe the serum sulfatide changes in STEMI patients. The STEMI patients were divided into two groups based on their value (15.2 µmol/L) of serum sulfatides upon admission. Patients' baseline characteristic data were collected, including clinically significant history, biochemical panel, and medication history. Among others, patients' LDL-C and HDL-C are in the same range, which established the comparability in two groups of patients. We found the correlations between a high level of serum sulfatides and the incidences of in-hospital death, late TVR, and overall MACE in patients with STEMI, but not with HDL-C and LDL-C levels. In future studies, we are going to seek to discover the relevant mechanisms.
In our prior study, we found a strong correlation among the levels of serum sulfatides and the risk of CVD in end-stage renal failure patients14, 22). Although the changes of serum sulfatides in the current study seem to be contradictory to our prior study, we believe end-stage renal failure and STEMI are different pathological processes, even patients with end-stage renal failure undergoing maintenance hemodialysis frequently present higher CVD risk and lower cholesterol level23, 24). In patients with end-stage renal failure, we think that high CVD risk is caused by many factors, including hemodialysis, blood lipids, inflammation, vascular endothelial damage, and hypotension. Meanwhile severe blood lipid loss may partly contribute to low serum sulfatides in patients. However, in patients with atherosclerosis, we and other studies found a positive correlation between serum sulfatide levels and human atherosclerotic lesions formation12, 20). Current study suggested that sulfatides also are involved in the late stage of severe coronary atherosclerosis, even the prognosis of STEMI. We are glad that this clinical study revealed more prospective on the function of sulfatides.
About the relationship between serum sulfatides and renal function in coronary heart disease (CHD) patients. Recently, Charoen reported their Mendelian randomization study of the influence of eGFR on coronary disease. They observed that eGFR (< 60 mL/min) is significantly negatively associated with CHD25), which is consistent with some other studies of eGFR-CHD association26). More interestingly, Sidana et al. found that in 207 patients with partial nephrectomy, most patients developed creatine kinase elevations > 2000 IU/L, whereas others had a greater decline in eGFR27). The present study results suggested that patients with serum sulfatides level above the median were significantly associated with decreased eGFR and increased CPK. The significant inverse correlation between serum sulfatides and eGFR may shed light on understanding sulfatides in the development of CVD. Higher serum sulfatides cause lower eGFR, which directly impacts the heart function. This may explain why high sulfatide levels lead to more incidences of TVR and overall MACE over the long-term. The pathophysiological mechanism between a high level of serum sulfatides and decreased eGFR in the STEMI patients should be further explored.
In the current study, hs-CRP was not recognized as a crucial and free marker for late TVR and, in turn, overall MACE. A significant restriction of hs-CRP is its deficient specificity. Raised hs-CRP levels as a systemic acute phase reactant are frequently noted with conditions, including infections, except atherosclerosis28). Serum sulfatides are raised in the acute phase of cardiovascular disease but not in common acute inflammatory diseases in which hs-CRP levels are increased11, 14, 19). Therefore, serum sulfatides may be useful prognostic biomarkers, even in STEMI patients complicated by acute inflammatory diseases.
We clearly know that this study has limitations. This was a single-center study with a relatively limited number of patients in each group; however, the statistical significance indicates the important role of sulfatides in STEMI patients. Further large-scale multicenter studies are needed to validate the prognostic value of serum sulfatides after STEMI.
Conclusions
The incidences of in-hospital death, late TVR, and, in turn, overall MACE in patients with STEMI were significantly associated with high level of serum sulfatides. Although additional clinical studies are needed, the sulfatide-dependent pathway could be a new target for the prevention and/or treatment of STEMI.
Acknowledgment
This work was supported by the National Natural Science Foundation of China (81370316) and (81601858).
Conflict of Interest
The authors report no relationships that could be construed as a conflict of interest.
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