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Remnant cholesterol predicts periprocedural myocardial injury following percutaneous coronary intervention in poorly-controlled type 2 diabetes
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JJCC-1447; No. of Pages 8 Journal of Cardiology xxx (2016) xxx–xxx
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Original article
Remnant cholesterol predicts periprocedural myocardial injury following percutaneous coronary intervention in poorly-controlled type 2 diabetes Rui-Xiang Zeng (MMed)a,b,1, Sha Li (MD, PhD)a,1, Min-Zhou Zhang (MD, PhD)b,1, Xiao-Lin Li (MD, PhD)a, Cheng-Gang Zhu (MD, PhD)a, Yuan-Lin Guo (MD, PhD)a, Yan Zhang (MD, PhD)a, Jian-Jun Li (MD, PhD)a,* a
Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China b Guangdong Provincial Hospital of Chinese Medicine & The 2nd Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 6 April 2016 Accepted 15 December 2016 Available online xxx
Background: Remnant cholesterol (RC) is receiving increasing attention regarding its relation to cardiovascular risk. Whether RC is associated with periprocedural myocardial injury (PMI) following percutaneous coronary intervention (PCI) in type 2 diabetes (T2D) is currently unknown. Methods: We prospectively enrolled 1182 consecutive T2D patients who were scheduled for PCI but with baseline normal preprocedural cardiac troponin I (cTnI). Patients were divided according to their glycemic control status: group A [glycated hemoglobin (HbA1c) < 7%, n = 563] and group B (HbA1c 7%, n = 619). PMI was evaluated by cTnI analysis within 24 h. The associations of preprocedural RC and the RC to high-density lipoprotein cholesterol ratio (RC/HDL-C) with PMI were investigated. Results: The associations of RC and RC/HDL-C with PMI were observed in group B (both p < 0.05) but not in group A (both p > 0.05). Patients in group B, a 1-SD increase of RC produced 30% and 32% increased risk for postprocedural cTnI > 3 upper limit of normal (ULN) and >5 ULN, respectively. The odds ratios for RC/HDL-C were the highest compared with any cholesterol fractions including total cholesterol (TC)/ HDL-C, low density lipoprotein cholesterol (LDL-C)/HDL-C, nonHDL-C/HDL-C, and triglyceride/HDL-C with 1.43 [95% confidence interval (CI): 1.10–1.88] for >3 ULN and 1.49 (95% CI: 1.13–1.97) for >5 ULN. However, no such associations were found in group A. Furthermore, patients with RC >27.46 mg/dL (third tertile) [RC 14.15 mg/dL (first tertile) as reference] were associated with a 1.57-fold and 2-fold increased risk for >3 ULN and >5 ULN in group B, respectively. Conclusions: RC and RC/HDL-C might be valuable, independent predictors for PMI in poorly-controlled diabetic patients undergoing PCI. ß 2017 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
Keywords: Remnant cholesterol Remnant cholesterol to HDL cholesterol ratio Type 2 diabetes Periprocedural myocardial injury Percutaneous coronary intervention
Introduction Percutaneous coronary intervention (PCI) is one of the dominant methods for coronary revascularization in patients with coronary artery disease (CAD). Even though technical advances in PCI result in a safe procedure with minimal complications, PCI is frequently accompanied with periprocedural myocardial injury (PMI),
* Corresponding author at: Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. Tel.: +86 10 88396077; fax: +86 10 68331730. E-mail address: [email protected] (J.-J. Li). 1 These authors contributed equally to this study.
especially with the use of high-sensitivity troponin [1]. Moreover, it has been well established that PMI is associated with increased subsequent mortality [2–4]. More importantly, previous studies suggested that patients with type 2 diabetes (T2D) had a 3-fold increased risk of CAD compared with normal subjects [5], and diabetic patients were also more prone to PMI as well as worse long-term outcome compared to those without diabetes [6]. Dyslipidemia is a common feature of diabetes and it is known to increase the risk of mortality and morbidity in diabetic patients [7]. Remnant cholesterol (RC) is defined as the cholesterol content of a subset of the triglyceride-rich lipoproteins called remnants, and associated with increased risk of cardiovascular disease [8–11]. The major triglyceride-rich lipoprotein in fasted subjects is very low density lipoproteins (VLDL) and to a lesser extent intermediate
http://dx.doi.org/10.1016/j.jjcc.2016.12.010 0914-5087/ß 2017 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
Please cite this article in press as: Zeng R-X, et al. Remnant cholesterol predicts periprocedural myocardial injury following percutaneous coronary intervention in poorly-controlled type 2 diabetes. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2016.12.010
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density lipoproteins (IDL), both apoB-100 containing, while in nonfasted subjects, VLDL in addition to chylomicron and VLDL remnants contribute to the pool [12]. Recently, studies have demonstrated that even after lowering low-density lipoprotein cholesterol (LDL-C) to recommended levels, there is a considerable residual risk of cardiovascular disease, and elevated RC levels may be one of the potential reasons [13]. In addition, elevated RC is also associated with reduced high-density lipoprotein cholesterol (HDL-C) [8], but it is also known that increased HDL-C levels have no benefit to reduce cardiovascular disease [14]. Therefore, elevated RC is likely to be a more potential causal factor than reduced HDL-C [8]. Of note, whether RC or RC/HDL-C was associated with PMI following PCI in patients with T2D is currently unknown, and the present study aimed to investigate these associations.
Methods Study population Between December 2010 and February 2014, 1252 consecutive diabetic patients with normal cardiac troponin I (cTnI) and creatine kinase-MB (CK-MB) levels without acute myocardial infarction (AMI) in the past 4 weeks who attempted to undergo elective PCI at our center were eligible for this study. The flowchart of inclusion and exclusion criteria for this study is demonstrated in Fig. 1. Finally, 1182 subjects (70.9% men, mean age 59.5 9.3 years) were effectively included in the present study. The study complied with the Declaration of Helsinki, and was approved by the hospital ethic review board (FuWai Hospital & National Center for Cardiovascular Diseases, Beijing, China). Informed written consent was obtained from all patients included in this study. Inclusion criteria: ♦ Over 18 years of age ♦ Type 2 diabetes underwent elecve PCI ♦ Normal cardiac markers before PCI
Several guidelines suggest that the glycemic control goal is glycated hemoglobin (HbA1c) < 7% in diabetic patients [15,16]. Based on a cut-off of 7% for HbA1c, patients were divided into two groups: group A (HbA1c < 7%, n = 563, well-controlled) and group B (HbA1c 7%, n = 619, poorly-controlled). Definitions Adult patients with T2D were identified according to 2009 American Diabetes Association criteria for diabetes diagnosis: fasting plasma glucose (FPG) 126 mg/dL (7.0 mmol/l) or symptoms of hyperglycemia and a casual (random) plasma glucose 200 mg/dL (11.1 mmol/l) or 2-h plasma glucose 200 mg/dL (11.1 mmol/l) during an oral glucose tolerance test (OGTT). Atherogenic index of plasma (AIP) was defined as lg (triglyceride/HDL-C). Non-HDL-C was characterized as TC minus HDL-C. RC was equal to non-HDL-C minus LDL-C. Angiographic success of PCI was defined as residual stenosis less than 20% with stenting and residual stenosis less than 50% with balloon angioplasty only by visual estimation. Unstable angina was defined as rest angina, new-onset severe angina, and increasing angina within 2 months. PMI was defined as postprocedural cTnI >3 upper limit of normal (ULN), which was the diagnosis criterion of periprocedural myocardial infarction published in 2007 and postprocedural cTnI >5 ULN which was a requirement in the arbitrarily revised diagnosis criteria published in 2012 [17,18]. Percutaneous coronary intervention The indication of PCI was based on the American College of Cardiology/American Heart Association (ACC/AHA) recommendations [19,20] and was performed by experienced interventional
Consecuve paents underwent PCI n = 6588
♦ Without AMI in the past 4
weeks ♦ Without cardiac dysfuncon ♦ Wrien informed consent
Eligible paents n = 1252
Finally enrolled paents n = 1182
Group A Well-controlled diabec paents (HbA1c <7%) n=563
70 were not eligible: ♦ 42 were excluded because a total chronic occlusion could not be crossed with a wire ♦ 3 paents were excluded because a subtotal chronic occlusion could not be crossed with a wire ♦ 6 paents were excluded because a severely calcified or tortuous lesion could not be crossed with a balloon ♦ 5 paents were excluded because were treated with they atheroablave, distal protecon or aspiraon devices thrombectomy ♦ 12 paents were excluded because the Remnant cholesterol values were negave ♦ 2 paents were excluded because lipid parameters were lost
Group B Poorly-controlled diabec paents (HbA1c ≥7%) n=619
Fig. 1. Inclusion and exclusion criteria for this study. PCI, percutaneous coronary intervention; AMI, acute myocardial infarction; HbA1c, glycated hemoglobin.
Please cite this article in press as: Zeng R-X, et al. Remnant cholesterol predicts periprocedural myocardial injury following percutaneous coronary intervention in poorly-controlled type 2 diabetes. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2016.12.010
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cardiologists. Before the procedure, all of the patients without contraindications received 100 mg of aspirin daily or a loading dose of 300 mg depending on whether they had already taken daily aspirin for at least 3 days, and they received 75 mg of clopidogrel daily or a loading dose of 300 mg depending on whether they had already taken clopidogrel for at least 3 days prior to intervention. All of the patients received either 5000 U or 70 U/kg bolus of unfractionated heparin just before the procedure and an additional bolus of 2000 to 3000 U were given every hour if the procedure lasted for more than an hour. Vascular access and PCI type (angioplasty only, angioplasty and stenting, or primary stenting) were determined by the interventional cardiologist according to the patient characteristics. Total balloon inflation times and inflation pressures were determined by the interventional cardiologist according to the technical properties of the balloon and the stent. After the procedure, all of the patients continued with aspirin and clopidogrel therapy daily. Use of glycoprotein IIb/ IIIa receptor antagonists or anticoagulants was at the discretion of the interventional cardiologist. Electrocardiogram monitoring All patients received a 12-lead electrocardiogram record before PCI, immediately after PCI, and in the case of symptoms that were interpreted as postprocedural ischemic events. All of the patients received continuous electrocardiogram monitoring using wireless technology after PCI during hospitalization. Biochemical measurements Fasting venous blood samples were obtained after at least a 12hour fast in the morning before intervention for measurement of fasting glucose levels, HbA1c, CK-MB activity, and the lipid profile. CTnI levels were determined in venous blood samples before PCI,
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24 hours after PCI, and in the event of symptoms or signs suggestive of myocardial ischemia. CTnI was analyzed using an immunochemiluminometric assay (Access AccuTnI, Beckman Coulter, Brea, CA, USA), the limit of detection was 0.01, and the total imprecision at the 99th percentile value was 14% [21]. The LDL-C concentration was analyzed using the selective solubilization method (1.006 < d < 1.063 g/ml, LDL test kit, Kyowa Medex, Tokyo, Japan). The HDL-C concentration was determined by a homogeneous method (Determiner HDL, Kyowa Medex). RC was calculated as TC minus HDL-C minus LDL-C, which reflected VLDL and chylomicrons in the present study. Plasma HbA1c and glucose levels were determined with conventional standard techniques. The ULN was defined as the 99th percentile of the normal population, with a total imprecision of <10%. The ULN of this test was 0.04 ng/ml. The peak cTnI value within 24 hours after the procedure was used for statistical analysis. Statistical analysis The data were presented as the mean SD, the median with interquartile ranges, or frequencies with percentages, as appropriate. Comparisons were made with independent-sample T tests, chisquare tests, Kruskal–Wallis tests, or Friedman tests as appropriate. Spearman rank correlation analyses were performed to determine the relationship between clinical parameters and postprocedural cTnI levels. Because plasma cTnI levels were not normally distributed, logtransformation was applied. Successful normalization of cTnI after log-transformation was evaluated using the Kolmogorov–Smirnov test. In logistic regression analyses, we used several multivariable models to examine the association of RC and RC/HDL-C levels with the occurrence of postprocedural cTnI elevation above various multiples of ULN in a hierarchical fashion. Specially, model 1 indicated the association with no adjustment for any confounding
Fig. 2. Adjusted impact of RC levels and RC/HDL ratio on postprocedural cTnI elevation in group B. RC, remnant cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; HbA1c, glycated hemoglobin; OR, odds ratio; cTnI, cardiac troponin I; ULN, upper limit of normal. Group B: HbA1c 7%, poorly controlled diabetes. Multivariate logistic regression model was adjusted for age, gender, body mass index, left ventricular ejection fraction, prior myocardial infarction, Gensini score, glucose, high-sensitivity C-reactive protein, intensity of statins, maximum inflation time, and number of postdilatations.
Please cite this article in press as: Zeng R-X, et al. Remnant cholesterol predicts periprocedural myocardial injury following percutaneous coronary intervention in poorly-controlled type 2 diabetes. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2016.12.010
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Table 1 Baseline clinical characteristics of the study population according to glycemic control. Group A (n = 563)
Variable Clinical characteristics Age, years Male, n (%) BMI, kg/m2 Hypertension, n (%) Dyslipidemia, n (%) Smoker, n (%) Family History of CAD, n (%) Unstable angina, n (%) LVEF, % Prior MI, n (%) Prior PCI, n (%) Prior CABG, n (%) TC, mg/dL LDL-C, mg/dL HDL-C, mg/dL NonHDL-C, mg/dL TC/HDL-C LDL-C/HDL-C NonHDL-C/HDL-C Triglyceride/HDL-C RC, mg/dL RC/HDL-C Triglyceride, mg/dL AIP HbA1c, % HbA1c, mmol/mol Glucose, mmol/L NT-proBNP, fmmol/L Creatinine, mmol/L Peak cTnI, ng/ml Hs-CRP, mg/L Hemoglobin, g/L Gensini score Prior treatment Statins, n (%)
Group B (n = 619)
p-value
60.16 9.50 401 (71.2) 26.30 3.03 410 (72.8) 479 (85.2) 307 (54.5) 133 (23.6)
58.88 9.05 437 (70.6) 26.70 3.28 431 (69.6) 514 (83.0) 328 (53.0) 127 (20.5)
0.018 0.848 0.029 0.247 0.339 0.598 0.206
300 (53.3) 64.02 6.60 37 (6.6) 165 (29.3) 22 (3.9) 154.45 38.64 90.88 31.81 40.25 9.39 114.20 36.62 3.97 1.14 2.34 0.89 2.97 1.14 4.09 2.81 23.32 14.24 0.63 0.46 136 (104–178) 0.54 0.25 6.43 0.39 46.82 4.25 5.91 1.19 529 (414–701) 77.01 16.66 0.06 (0.02–0.20) 1.56 (0.92–3.32) 139.12 14.87 32 (18–53)
300 (48.5) 63.05 6.73 62 (10.0) 172 (27.8) 17 (2.7) 163.40 42.09 96.27 33.25 39.81 10.20 123.59 39.91 4.26 1.21 2.50 0.89 3.26 1.21 4.87 4.23 27.31 22.14 0.75 0.68 142 (106–204) 0.59 0.27 8.24 1.15 66.56 12.53 7.76 2.38 538 (430–707) 75.25 15.27 0.05 (0.01–0.20) 1.98 (1.00–3.55) 140.34 14.63 37 (20–58)
556 (98.8)
609 (98.4)
0.917
Types Atorvastatin, n (%) Rosuvastatin, n (%) Simvastatin, n (%) Pravastatin, n (%) Fluvastatin, n (%) Pitavastatin, n (%)
299 67 137 25 11 17
(53.1) (11.9) (24.3) (4.4) (1.9) (3.0)
315 73 152 28 18 23
(50.9) (11.8) (24.6) (4.5) (2.9) (3.7)
0.224 0.975 0.889 0.701 0.311 0.476
Intensity of statins High-intensity, n (%) Moderate-intensity, n (%) Low-intensity, n (%) Aspirin, n (%) Clopidogrel, n (%) b-Blockers, n (%) Calcium blockers, n (%) ACE inhibitors, n (%) ARBs, n (%)
19 (3.4) 500 (88.8) 37 (6.6) 559 (99.3) 563 (100) 502 (89.2) 292 (52.0) 172 (30.6) 184 (32.7)
19 517 73 618 619 540 300 182 208
(3.1) (83.5) (11.8) (100) (100) (87.2) (48.5) (29.4) (33.6)
0.624 0.035 0.010 0.882 0.999 0.512 0.127 0.534 0.578
0.057 0.014 0.036 0.606 0.328 <0.001 0.004 0.435 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.003 <0.001 <0.001 <0.001 <0.001 0.538 0.059 0.144 0.015 0.157 0.034
Values are expressed as the mean SD, the median with interquartile range or n (%). Group A: HbA1c < 7%, well-controlled diabetes; Group B: HbA1c 7%, poorly controlled diabetes. The bold values indicate p < 0.05. High-intensity of statins was patients with atorvastatin 40 mg to 80 mg, or resuvastatin 20 mg to 40 mg; Moderate-intensity therapy was patients daily with atorvastatin 10 mg to 20 mg, or resuvastatin 5 mg to 10 mg, or simvastatin 20 mg to 40 mg; or pravastatin 40 mg to 80 mg; or fluvastatin 80 mg, or pitavastatin 2 mg to 4 mg; Low-intensity therapy was patients with simvastatin 10 mg; or pravastatin 10 mg to 20 mg; or fluvastatin 20 mg to 40 mg, or pitavastatin 1 mg. BMI, body mass index; CAD, coronary artery disease; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; TC, Total Cholesterol; LDL-C, low-density lipoprotein cholesterol; RC, remnant cholesterol; HDL-C, high-density lipoprotein cholesterol; AIP, atherogenic index of plasma; HbA1c, glycated hemoglobin; NTpro-BNP, N-terminal pro-brain natriuretic peptide; CTnI, cardiac troponin I; HsCRP, high-sensitivity C-reactive protein; ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers.
factors, model 2 was with the adjustment for the conventional risk factors such as age and gender, and model 3 was designed to adjust for the conventional risk factors plus the variables that were significantly associated with postprocedural cTnI in the present population with a p-value <0.05. Besides, the multivariable models to examine the association of RC and RC/HDL-C tertiles (Fig. 2) were the same as model 3. A 2-tailed p-value of <0.05 was considered to be statistically significant. All of the analyses were performed using SPSS version 19.0 software (Chicago, IL, USA).
Results Baseline and procedural characteristics Finally, 1182 patients were included in this analysis. Table 1 demonstrates the baseline clinical characteristics of diabetic patients according to the control status of diabetes. Group A (n = 563) was defined as patients with HbA1c <7%, well-controlled diabetes; Group B (n = 619) was characterized as HbA1c 7%, poorly-controlled diabetes. As shown in Table 1, when compared to group B, patients in group A were older with a lighter weight (both p < 0.05). Moreover, patients in group A had less prior MI, lower high-sensitivity C-reactive protein levels, Gensini score (the coronary extent scoring system), but higher left ventricular ejection fraction (LVEF) than those in group B (all p < 0.05). Table 2 shows the procedural characteristics. Patients in group A had more maximum inflation time and received fewer balloons postdilatation (both p < 0.05). However, no significant differences were observed in vascular access, target vessels, target lesion sites, bifurcation lesions, in-stent restenosis, kissing balloon use, target lesion types, stent numbers, total stent lengths, predilation times, maximum inflation pressure, and maximum inflation times among the two groups (all p > 0.05). Table 2 Procedural characteristics of the study population according to glycemic control. Procedural characteristics Transradial access, n (%) Target vessel Left main Left anterior descending Left circumflex Right coronary artery Grafts Lesion location Proximal Middle Distal Branch Lesion classification ACC/AHA type A/B1 ACC/AHA type B2/C Final TIMI III flow, n (%) Bifurcation lesions, n (%) Use of kissing balloon, n (%) Occlusion lesions, n (%) In-stent restenosis, n (%) Number of stents implanted Total stent length, mm Maximum pressure, atm Maximum inflation time, s Number of predilations Number of postdilatations
Group A (n = 563)
Group B (n = 619)
p-value
502 (89.2)
559 (90.3)
0.565
29 317 183 215 3
(5.2) (56.3) (32.5) (38.2) (0.5)
24 353 201 238 1
(3.9) (57.0) (32.5) (38.4) (0.2)
0.326 0.814 0.999 0.952 0.352
286 358 166 139
(50.8) (63.6) (29.5) (24.7)
344 402 173 165
(55.6) (64.9) (28.1) (26.7)
0.199 0.476 0.869 0.883
165 (26.8) 491 (79.3) 601 (97.1) 232 (37.5) 51 (8.2) 94 (14.9) 24 (3.9) 1.97 1.02 43.98 27.04 17.75 3.53 9.62 3.57 3.0 (1.0–5.0) 4.0 (3.0–7.0)
0.449 0.195 0.894 0.933 0.666 0.505 0.724 0.891 0.542 0.701 0.011 0.186 0.038
164 (29.2) 437 (77.8) 553 (98.2) 213 (37.9) 42 (7.5) 74 (13.1) 27 (4.8) 1.96 1.05 43.03 26.38 17.84 3.80 10.21 4.39 2.0 (1.0–5.0) 4.0 (2.0–6.0)
Values are expressed as the mean SD, the median with interquartile range or n (%). Group A: HbA1c < 7%, well-controlled diabetes; Group B: HbA1c 7%, poorly controlled diabetes. The bold values indicate p < 0.05. ACC, American College of Cardiology; AHA, American Heart Association; TIMI, thrombolysis in myocardial infarction.
Please cite this article in press as: Zeng R-X, et al. Remnant cholesterol predicts periprocedural myocardial injury following percutaneous coronary intervention in poorly-controlled type 2 diabetes. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2016.12.010
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JJCC-1447; No. of Pages 8 R.-X. Zeng et al. / Journal of Cardiology xxx (2016) xxx–xxx
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and RC/HDL-C levels had higher postprocedural cTnI levels (r = 0.099, p = 0.014 and r = 0.109, p = 0.007, respectively).
Lipid parameters and PMI As shown in Table 1, the levels of TC, LDL-C, nonHDL-C, triglyceride, AIP, RC and RC/HDL-C, TC/HDL-C, LDL-C/HDL-C, nonHDL-C/HDL-C, and triglyceride/HDL-C were significantly different between group A and B (p < 0.05). The associations of lipid parameters with PMI were investigated respectively on the basis of the glycemic control status (Table 3). Interestingly, the associations of lipid parameters with PMI were presented differently between patients with well-controlled diabetes and patients with poorly-controlled diabetes (Table 3). In group A, that was the group of well-controlled diabetes, except for the AIP and triglyceride (p < 0.05), the lipid parameters including RC, RC/HDL-C, TC/HDL-C, LDL-C/HDL-C, nonHDL-C/HDL-C, and triglyceride/HDL-C showed no significant association with PMI (all p > 0.05). The LVEF were also not different between the four groups divided by PMI (p > 0.05). In group B, that was the group of poorly-controlled diabetes, however, the lipid parameters including RC, RC/HDL-C, AIP, TC/HDL-C, nonHDL-C/HDL-C, and triglyceride/HDL-C were significantly and positively related to PMI (all p < 0.05). Moreover, the data from Spearman rank correlation analyses (not shown in the Table) consistently revealed that both RC and RC/ HDL-C levels had no association with postprocedural cTnI levels in group A, while in group B, patients with higher preprocedural RC
Logistic regression analysis In a univariate logistic regression analysis, we determined that RC (per 1-SD increase) and RC/HDL-C were significantly associated with a greater risk of postprocedural cTnI elevation above 3 ULN and 5 ULN in group B, but not in group A (Table 4, Model 1). After adjustment for age and gender, we found a similar result to the unadjustment model (Table 4, Model 2). Meanwhile, we further determined the independent associations between RC or RC/HDL-C and the development of postprocedural cTnI elevation. As a result, in group B, a 1-SD increase in RC produced 30% and 32% increased risk of postprocedural cTnI >3 ULN and >5 ULN, respectively, but not in group A. Importantly, the causal odds ratio (OR) for RC/ HDL-C was 1.43 [95% confidence interval (CI): 1.10 to 1.88) and 1.49 (95% CI: 1.13 to 1.97) in group B with postprocedural cTnI >3 ULN and >5 ULN, respectively, presenting the highest values when compared to the other cholesterol fractions including TC/ HDL-C, LDL-C/HDL-C, nonHDL-C/HDL-C, and triglyceride/HDL-C (Table 4, Model 3). Furthermore, in a multivariate logistic regression model, patients with RC levels >27.46 mg/dL (third tertile) compared with RC levels 14.15 mg/dL (first tertile) were associated with a
Table 3 Parameters in group A and group B according to postprocedural cTnI elevation. Variable Group A n (%) TC, mg/dL LDL-C, mg/dL HDL-C, mg/dL RC, mg/dL NonHDL-C, mg/dL RC/HDL-C TC/HDL-C LDL-C/HDL-C NonHDL-C/HDL-C Triglyceride/HDL-C Triglyceride, mg/dL HbA1c, % NT-proBNP, fmmol/L AIP Gensini score LVEF, % TIMI III, n (%) Group B n (%) TC, mg/dL LDL-C, mg/dL HDL-C, mg/dL RC, mg/dL NonHDL-C, mg/dL RC/HDL-C TC/HDL-C LDL-C/HDL-C NonHDL-C/HDL-C Triglyceride/HDL-C Triglyceride, mg/dL HbA1c, % NT-proBNP, fmmol/L AIP Gensini score LVEF, % TIMI III, n (%)
cTnI elevation 1 ULN
1 ULN < cTnI elevation 3 ULN
3 ULN < cTnI elevation 5 ULN
cTnI elevation > 5 ULN
240 (42.6) 153.24 38.00 89.44 30.98 39.34 8.85 24.46 16.98 113.91 36.29 0.68 0.55 4.04 1.19 2.35 0.91 3.04 1.19 4.56 3.49 148 (106–185) 6.44 0.37 514 (402–637) 0.58 0.26 20 (4–40) 63.89 6.73 237 (97.5)
117 (20.8) 151.16 34.47 88.11 28.84 41.12 10.12 21.93 10.00 110.04 31.18 0.59 0.34 3.80 0.95 2.22 0.76 2.80 0.95 3.60 2.03 122 (102–159) 6.43 0.39 550 (440–757) 0.50 0.23 20 (5–47) 64.77 6.93 115 (98.2)
63 (11.2) 160.03 41.94 95.66 34.86 39.57 7.99 24.80 13.57 120.46 39.75 0.66 0.37 4.13 1.11 2.47 0.95 3.13 1.11 4.03 2.17 144 (105–186) 6.49 0.36 526 (398–647) 0.55 0.21 24 (4–45) 64.12 5.05 62 (98.4)
143 (25.4) 154.45 38.64 93.45 33.95 41.39 10.09 21.89 12.20 115.34 39.66 0.58 0.38 3.94 1.19 2.35 0.95 2.94 1.19 3.73 2.17 123 (99–170) 6.40 0.43 557 (429–749) 0.50 0.25 26 (6–50) 63.55 6.73 139 (97.2)
0.409 0.293 0.126 0.189 0.320 0.116 0.206 0.307 0.206 0.060 0.017 0.464 0.051 0.009 0.531 0.511 0.741
290 (46.8) 158.55 40.61 93.42 32.65 40.34 9.50 24.80 17.16 118.22 38.35 0.67 0.57 4.05 1.14 2.39 0.85 3.05 1.14 4.43 3.62 135 (103–194) 8.31 1.22 513 (425–650) 0.56 0.26 20 (4–45) 63.27 7.29 284 (97.9)
129 (20.8) 165.46 45.34 98.70 36.27 39.24 12.06 27.52 25.94 126.22 43.21 0.80 0.82 4.44 1.41 2.64 1.02 3.44 1.41 4.93 3.84 146 (107–205) 8.25 1.12 545 (446–709) 0.60 0.28 28 (6–47) 62.14 5.86 125 (96.9)
44 (7.1) 169.16 38.74 99.87 34.28 40.99 8.91 28.30 27.22 128.17 38.51 0.76 0.82 4.28 1.20 2.52 0.95 3.28 1.20 5.02 5.98 138 (107–201) 8.02 0.96 508 (428–804) 0.57 0.30 23 (7–58) 63.58 5.84 42 (95.5)
156 (25.2) 169.07 42.25 98.56 31.31 38.97 10.14 31.54 24.77 130.10 39.33 0.87 0.69 4.48 1.14 2.61 0.81 3.48 1.14 5.61 4.91 155 (109–233) 8.17 1.08 572 (431–821) 0.644 0.29 32 (8–52) 63.26 6.53 150 (96.1)
0.050 0.253 0.421 0.023 0.014 0.021 0.001 0.015 0.001 0.044 0.069 0.378 0.036 0.019 0.043 0.392 0.649
p-value
Group A: HbA1c < 7%, well-controlled diabetes; Group B: HbA1c 7%, poorly controlled diabetes. The bold values indicate p < 0.05. TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; RC, remnant cholesterol; HDL-C, high-density lipoprotein cholesterol; HbA1c, glycated hemoglobin; NTpro-BNP, N-terminal pro-brain natriuretic peptide; CTnI, cardiac troponin I; ULN, upper limit of normal; AIP, atherogenic index of plasma; LVEF, left ventricular ejection fraction; TIMI, thrombolysis in myocardial infarction.
Please cite this article in press as: Zeng R-X, et al. Remnant cholesterol predicts periprocedural myocardial injury following percutaneous coronary intervention in poorly-controlled type 2 diabetes. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2016.12.010
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Table 4 Logistic regression analysis of RC and RC/HDL-C for postprocedural cTnI elevation in group A and group B. Group A
Variable
Model 1 RC (per 1-SD increase) RC/HDL-C TC/HDL-C LDL-C/HDL-C NonHDL-C/HDL-C Triglyceride (per 10 mg/dL increase) Triglyceride/HDL-C Model 2 RC (per 1-SD increase) RC/HDL-C TC/HDL-C LDL-C/HDL-C NonHDL-C/HDL-C Triglyceride (per 10 mg/dL increase) Triglyceride/HDL-C Model 3 RC (per 1-SD increase) RC/HDL-C TC/HDL-C LDL-C/HDL-C NonHDL-C/HDL-C Triglyceride (per 10 mg/dL increase) Triglyceride/HDL-C
Group B
cTnI elevation > 3 ULN
cTnI elevation > 5 ULN
cTnI elevation > 3 ULN
cTnI elevation > 5 ULN
OR (95% CI)
OR (95% CI)
OR (95% CI)
OR (95% CI)
p-value
p-value
p-value
p-value
0.94 0.79 1.03 1.10 1.03 0.99 0.94
(0.79–1.12) (0.53–1.18) (0.88–1.19) (0.91–1.34) (0.88–1.19) (0.97–1.01) (0.88–1.01)
0.496 0.247 0.728 0.301 0.728 0.189 0.095
0.86 0.68 0.96 1.03 0.96 0.98 0.93
(0.69–1.06) (0.43–1.10) (0.81–1.14) (0.83–1.27) (0.81–1.14) (0.96–1.01) (0.86–1.01)
0.166 0.118 0.658 0.811 0.658 0.142 0.083
1.25 1.33 1.19 1.17 1.19 1.02 1.05
(1.06–1.48) (1.04–1.70) (1.04–1.37) (0.97–1.41) (1.04–1.37) (1.00–1.03) (1.01–1.09)
0.010 0.022 0.012 0.108 0.012 0.009 0.017
1.25 1.36 1.21 1.19 1.21 1.02 1.05
(1.06–1.49) (1.06–1.74) (1.05–1.41) (0.97–1.45) (1.05–1.41) (1.00–1.03) (1.01–1.09)
0.010 0.017 0.009 0.094 0.009 0.010 0.015
0.97 0.83 1.06 1.14 1.06 1.02 0.95
(0.81–1.16) (0.55–1.26) (0.90–1.23) (0.94–1.38) (0.90–1.23) (1.00–1.04) (0.89–1.02)
0.703 0.382 0.488 0.193 0.488 0.132 0.172
0.89 0.73 1.00 1.06 1.00 1.02 0.94
(0.71–1.09) (0.45–1.20) (0.84–1.19) (0.86–1.32) (0.84–1.19) (1.00–1.05) (0.87–1.02)
0.295 0.211 0.958 0.581 0.958 0.057 0.171
1.29 1.43 1.25 1.21 1.25 1.03 1.06
(1.09–1.53) (1.11–1.84) (1.08–1.44) (1.00–1.47) (1.08–1.44) (1.01–1.05) (1.02–1.11)
0.004 0.006 0.002 0.045 0.002 0.009 0.003
1.31 1.48 1.28 1.24 1.28 1.04 1.07
(1.10–1.56) (1.14–1.91) (1.10–1.49) (1.01–1.52) (1.10–1.49) (1.01–1.06) (1.02–1.11)
0.003 0.003 0.001 0.040 0.001 0.002 0.002
0.94 0.79 1.04 1.13 1.04 0.99 0.95
(0.78–1.14) (0.52–1.22) (0.88–1.24) (0.92–1.40) (0.88–1.24) (0.97–1.01) (0.88–1.02)
0.523 0.287 0.624 0.243 0.624 0.253 0.143
0.86 0.68 0.96 1.03 0.96 0.99 0.94
(0.68–1.08) (0.41–1.15) (0.79–1.16) (0.81–1.30) (0.79–1.16) (0.96–1.01) (0.87–1.03)
0.191 0.148 0.658 0.828 0.957 0.271 0.174
1.30 1.43 1.27 1.24 1.27 1.02 1.06
(1.08–1.56) (1.10–1.88) (1.09–1.47) (1.01–1.52) (1.09–1.47) (1.01–1.03) (1.02–1.11)
0.007 0.009 0.002 0.041 0.002 0.008 0.008
1.32 1.49 1.30 1.27 1.30 1.02 1.07
(1.09–1.60) (1.13–1.97) (1.11–1.54) (1.02–1.58) (1.11–1.54) (1.01–1.04) (1.02–1.12)
0.004 0.005 0.001 0.033 0.001 0.005 0.004
RC, remnant cholesterol; HDL-C, high-density lipoprotein cholesterol; HbA1c, glycated hemoglobin; LDL-C, low-density lipoprotein cholesterol; OR, odds ratio; CTnI, cardiac troponin I; ULN, upper limit of normal; BMI body mass index; LVEF, left ventricular ejection fraction; MI, myocardial infarction; hs-CRP, high-sensitivity C-reactive protein. Group A: HbA1c < 7%, well-controlled diabetes; SDs were 14.24 mg/dL for RC; Group B: HbA1c 7%, poorly-controlled diabetes; SDs were 22.14 mg/dL for RC; Model 1: no adjustment; Model 2: adjusted for age and gender; Model 3: adjusted for model 2+ BMI, LVEF, prior MI, Gensini score, glucose, hs-CRP, intensity of statins, maximum inflation time, number of postdilatations.
1.57-fold and 2-fold increased risk of postprocedural cTnI >3 ULN and >5 ULN in group B, respectively (Fig. 2). In addition, patients with RC/HDL-C ratio >0.74 (third tertile) compared with RC/HDL-C ratio 0.46 (first tertile) were associated with a 2.18fold and 2.65-fold increased risk of postprocedural cTnI >3 ULN and >5 ULN in group B, respectively (Fig. 2). Discussion In this study of patients with T2D undergoing PCI, we firstly investigated the effect of RC and RC/HDL-C on the risk of PMI. The main findings were as follows: (1) There were significant differences in levels of RC and RC/HDL-C between patients with well-controlled diabetes and poorly-controlled diabetes; (2) The associations of RC and RC/HDL-C with PMI could be observed in patients with poorly-controlled diabetes but not in the wellcontrolled group; (3) A 1-SD increase in RC produced 30% and 32% increased risk for postprocedural cTnI >3 ULN and >5 ULN, respectively, while the causal ORs were 1.43 (95% CI: 1.10 to 1.88) and 1.49 (95% CI: 1.13 to 1.97) for RC/HDL-C in poorly-controlled diabetes; Patients with RC levels >27.46 mg/dL (third tertile) compared with RC levels 14.15 mg/dL (first tertile) had a 1.57fold and 2-fold increased risk for postprocedural cTnI >3 ULN and >5 ULN in poorly-controlled diabetes, respectively; (4) Compared to the cholesterol fractions including TC/HDL-C, LDL-C/HDLC, nonHDL-C/HDL-C, and triglyceride/HDL-C, the predictive values of RC/HDL-C measured by the ORs for PMI seemed to be the highest. Therefore, these findings might indicate the different benefit to gain by reducing levels of RC in T2D between wellcontrolled and poorly-controlled groups, suggesting the clinical implications with the role of RC in the development and outcomes of diabetic patients with PCI and the need for large clinical
intervention trials examining if lowering of RC in individuals with elevated levels will reduce cardiovascular risk in diabetic populations. To date, risk factors for PMI can broadly be categorized as patient-related, lesion-related, and procedure-related [22]. However, the definite risk stratification of PMI following PCI remains uncertain. So our team paid more attention to the study about PMI, and previously demonstrated that nonHDL-C compared to LDL-C was a better predictor for PMI in poorly-controlled patients with T2D, and that increased preprocedural N-term pro-B-type natriuretic peptide (NT-pro-BNP) levels were strongly and independently associated with the higher risk of PMI [23,24]. Furthermore, several studies reported that remnant lipoproteins were associated with increased risk for cardiovascular disease [8,9,25–30]. A study from Varbo et al. [8] suggested that elevated levels of RC and increased ratio of RC to HDL-C were associated with increased risk of ischemic heart disease in the general population. In this study, for the further convenience of risk stratification of PMI related to PCI, we firstly revealed the associations between RC levels, RC/HDL-C ratio or other lipid profiles ratio, and PMI following PCI in poorly-controlled diabetic patients, might provide one of the mechanisms of adverse outcomes following PCI in poorly-controlled diabetics, which differed from our previous study. It has been well established that T2D is associated with varied lipid abnormalities, including increased remnant lipoproteins, which may cause macrovascular complications [31–33]. RC is the cholesterol content of triglyceride-rich lipoproteins, and is higher in diabetic patients with CAD [31,34]. Triglyceride-rich lipoproteins are of particular importance in diabetic populations because insulin resistance increases hepatic VLDL production and decreases clearance of triglyceride-rich lipoproteins [35]. In the
Please cite this article in press as: Zeng R-X, et al. Remnant cholesterol predicts periprocedural myocardial injury following percutaneous coronary intervention in poorly-controlled type 2 diabetes. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2016.12.010
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present study, the majority of RC were VLDL and chylomicron remnants. the Penn Diabetes Heart Study reported that VLDLcholesterol was associated with coronary artery calcification independent of established cardiovascular risk factors [35]. Moreover, one study indicated that high levels of remnant-like lipoprotein particles cholesterol had a crucial role in the pathogenesis of CAD in T2D, and remnant lipoproteinemia represented a risk factor that should be a therapeutic target in diabetic patients [29]. However, we found the association of both RC and RC/HDL-C levels with increased PMI risk in poorlycontrolled diabetes but not well-controlled diabetes. Although the exact mechanism was unclear, the potential reason for explaining the disparity might be related to the glycemic control. A study reported that improved glycemic control could promote lipid homeostasis in T2D by lowering triglyceride levels and causing a favorable change in HDL and LDL composition [36]. Thus, the findings of the present study might also point out the importance of glycemic control in diabetic patients who underwent PCI. To our knowledge, the definite explanations for a causal effect of elevated RC on PMI in poorly-controlled T2D are unclear. However, previous studies might give certain clues. For example, research reported that remnant-like lipoprotein particle cholesterol increases production of tissue factor, which is essential for the thrombotic events in endothelial cells [29,37] and enhances aggregation of platelets [38]. In addition, one study demonstrated the causal association of non-fasting RC with low-grade inflammation, which may be involved in atherogenesis [39], a disease with a known inflammatory nature [40]. Some limitations existed in this study. First, the cardiovascular events were not analyzed due to cross-sectional features of the study. Moreover, although we adjusted the multivariable analysis for factors that influence postprocedural cTnI levels, residual confounders and hidden comorbidities on PMI might have been not entirely eliminated. The analysis would be more valuable if it were done separately on all the available 24 h troponin values and on the incidence of periprocedural symptoms of ischemia and signs (including absolute troponin values measured in this subset). Besides, the present study lacked enough information regarding diabetes: such as, duration, microvascular complications, and treatment. Finally, there were different methods to assay for measuring remnant lipoproteins [29,41]. Our study used the calculation method [8,39], which might be not as precise as directly measuring remnants. Conclusion In conclusion, in poorly-controlled diabetic patients undergoing PCI, RC as well as RC/HDL-C might be independent predictors for PMI. Conversely, neither RC nor RC/HDL-C levels were associated with PMI in well-controlled diabetic patients. Funding This work was partially supported by the National Natural Scientific Foundation (81070171, 81241121), the Specialized Research Fund for the Doctoral Program of the Higher Education of China (20111106110013), the Capital Special Foundation of Clinical Application Research (Z121107001012015), the Capital Health Development Fund (2011400302), and the Beijing Natural Science Foundation (7131014) awarded to Dr Jian-Jun Li, MD, PhD. Conflicts of interest The authors have no conflicts of interest to disclose.
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Original article
Remnant cholesterol predicts periprocedural myocardial injury following percutaneous coronary intervention in poorly-controlled type 2 diabetes Rui-Xiang Zeng (MMed)a,b,1, Sha Li (MD, PhD)a,1, Min-Zhou Zhang (MD, PhD)b,1, Xiao-Lin Li (MD, PhD)a, Cheng-Gang Zhu (MD, PhD)a, Yuan-Lin Guo (MD, PhD)a, Yan Zhang (MD, PhD)a, Jian-Jun Li (MD, PhD)a,* a
Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China b Guangdong Provincial Hospital of Chinese Medicine & The 2nd Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 6 April 2016 Accepted 15 December 2016 Available online xxx
Background: Remnant cholesterol (RC) is receiving increasing attention regarding its relation to cardiovascular risk. Whether RC is associated with periprocedural myocardial injury (PMI) following percutaneous coronary intervention (PCI) in type 2 diabetes (T2D) is currently unknown. Methods: We prospectively enrolled 1182 consecutive T2D patients who were scheduled for PCI but with baseline normal preprocedural cardiac troponin I (cTnI). Patients were divided according to their glycemic control status: group A [glycated hemoglobin (HbA1c) < 7%, n = 563] and group B (HbA1c 7%, n = 619). PMI was evaluated by cTnI analysis within 24 h. The associations of preprocedural RC and the RC to high-density lipoprotein cholesterol ratio (RC/HDL-C) with PMI were investigated. Results: The associations of RC and RC/HDL-C with PMI were observed in group B (both p < 0.05) but not in group A (both p > 0.05). Patients in group B, a 1-SD increase of RC produced 30% and 32% increased risk for postprocedural cTnI > 3 upper limit of normal (ULN) and >5 ULN, respectively. The odds ratios for RC/HDL-C were the highest compared with any cholesterol fractions including total cholesterol (TC)/ HDL-C, low density lipoprotein cholesterol (LDL-C)/HDL-C, nonHDL-C/HDL-C, and triglyceride/HDL-C with 1.43 [95% confidence interval (CI): 1.10–1.88] for >3 ULN and 1.49 (95% CI: 1.13–1.97) for >5 ULN. However, no such associations were found in group A. Furthermore, patients with RC >27.46 mg/dL (third tertile) [RC 14.15 mg/dL (first tertile) as reference] were associated with a 1.57-fold and 2-fold increased risk for >3 ULN and >5 ULN in group B, respectively. Conclusions: RC and RC/HDL-C might be valuable, independent predictors for PMI in poorly-controlled diabetic patients undergoing PCI. ß 2017 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
Keywords: Remnant cholesterol Remnant cholesterol to HDL cholesterol ratio Type 2 diabetes Periprocedural myocardial injury Percutaneous coronary intervention
Introduction Percutaneous coronary intervention (PCI) is one of the dominant methods for coronary revascularization in patients with coronary artery disease (CAD). Even though technical advances in PCI result in a safe procedure with minimal complications, PCI is frequently accompanied with periprocedural myocardial injury (PMI),
* Corresponding author at: Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. Tel.: +86 10 88396077; fax: +86 10 68331730. E-mail address: [email protected] (J.-J. Li). 1 These authors contributed equally to this study.
especially with the use of high-sensitivity troponin [1]. Moreover, it has been well established that PMI is associated with increased subsequent mortality [2–4]. More importantly, previous studies suggested that patients with type 2 diabetes (T2D) had a 3-fold increased risk of CAD compared with normal subjects [5], and diabetic patients were also more prone to PMI as well as worse long-term outcome compared to those without diabetes [6]. Dyslipidemia is a common feature of diabetes and it is known to increase the risk of mortality and morbidity in diabetic patients [7]. Remnant cholesterol (RC) is defined as the cholesterol content of a subset of the triglyceride-rich lipoproteins called remnants, and associated with increased risk of cardiovascular disease [8–11]. The major triglyceride-rich lipoprotein in fasted subjects is very low density lipoproteins (VLDL) and to a lesser extent intermediate
http://dx.doi.org/10.1016/j.jjcc.2016.12.010 0914-5087/ß 2017 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
Please cite this article in press as: Zeng R-X, et al. Remnant cholesterol predicts periprocedural myocardial injury following percutaneous coronary intervention in poorly-controlled type 2 diabetes. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2016.12.010
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density lipoproteins (IDL), both apoB-100 containing, while in nonfasted subjects, VLDL in addition to chylomicron and VLDL remnants contribute to the pool [12]. Recently, studies have demonstrated that even after lowering low-density lipoprotein cholesterol (LDL-C) to recommended levels, there is a considerable residual risk of cardiovascular disease, and elevated RC levels may be one of the potential reasons [13]. In addition, elevated RC is also associated with reduced high-density lipoprotein cholesterol (HDL-C) [8], but it is also known that increased HDL-C levels have no benefit to reduce cardiovascular disease [14]. Therefore, elevated RC is likely to be a more potential causal factor than reduced HDL-C [8]. Of note, whether RC or RC/HDL-C was associated with PMI following PCI in patients with T2D is currently unknown, and the present study aimed to investigate these associations.
Methods Study population Between December 2010 and February 2014, 1252 consecutive diabetic patients with normal cardiac troponin I (cTnI) and creatine kinase-MB (CK-MB) levels without acute myocardial infarction (AMI) in the past 4 weeks who attempted to undergo elective PCI at our center were eligible for this study. The flowchart of inclusion and exclusion criteria for this study is demonstrated in Fig. 1. Finally, 1182 subjects (70.9% men, mean age 59.5 9.3 years) were effectively included in the present study. The study complied with the Declaration of Helsinki, and was approved by the hospital ethic review board (FuWai Hospital & National Center for Cardiovascular Diseases, Beijing, China). Informed written consent was obtained from all patients included in this study. Inclusion criteria: ♦ Over 18 years of age ♦ Type 2 diabetes underwent elecve PCI ♦ Normal cardiac markers before PCI
Several guidelines suggest that the glycemic control goal is glycated hemoglobin (HbA1c) < 7% in diabetic patients [15,16]. Based on a cut-off of 7% for HbA1c, patients were divided into two groups: group A (HbA1c < 7%, n = 563, well-controlled) and group B (HbA1c 7%, n = 619, poorly-controlled). Definitions Adult patients with T2D were identified according to 2009 American Diabetes Association criteria for diabetes diagnosis: fasting plasma glucose (FPG) 126 mg/dL (7.0 mmol/l) or symptoms of hyperglycemia and a casual (random) plasma glucose 200 mg/dL (11.1 mmol/l) or 2-h plasma glucose 200 mg/dL (11.1 mmol/l) during an oral glucose tolerance test (OGTT). Atherogenic index of plasma (AIP) was defined as lg (triglyceride/HDL-C). Non-HDL-C was characterized as TC minus HDL-C. RC was equal to non-HDL-C minus LDL-C. Angiographic success of PCI was defined as residual stenosis less than 20% with stenting and residual stenosis less than 50% with balloon angioplasty only by visual estimation. Unstable angina was defined as rest angina, new-onset severe angina, and increasing angina within 2 months. PMI was defined as postprocedural cTnI >3 upper limit of normal (ULN), which was the diagnosis criterion of periprocedural myocardial infarction published in 2007 and postprocedural cTnI >5 ULN which was a requirement in the arbitrarily revised diagnosis criteria published in 2012 [17,18]. Percutaneous coronary intervention The indication of PCI was based on the American College of Cardiology/American Heart Association (ACC/AHA) recommendations [19,20] and was performed by experienced interventional
Consecuve paents underwent PCI n = 6588
♦ Without AMI in the past 4
weeks ♦ Without cardiac dysfuncon ♦ Wrien informed consent
Eligible paents n = 1252
Finally enrolled paents n = 1182
Group A Well-controlled diabec paents (HbA1c <7%) n=563
70 were not eligible: ♦ 42 were excluded because a total chronic occlusion could not be crossed with a wire ♦ 3 paents were excluded because a subtotal chronic occlusion could not be crossed with a wire ♦ 6 paents were excluded because a severely calcified or tortuous lesion could not be crossed with a balloon ♦ 5 paents were excluded because were treated with they atheroablave, distal protecon or aspiraon devices thrombectomy ♦ 12 paents were excluded because the Remnant cholesterol values were negave ♦ 2 paents were excluded because lipid parameters were lost
Group B Poorly-controlled diabec paents (HbA1c ≥7%) n=619
Fig. 1. Inclusion and exclusion criteria for this study. PCI, percutaneous coronary intervention; AMI, acute myocardial infarction; HbA1c, glycated hemoglobin.
Please cite this article in press as: Zeng R-X, et al. Remnant cholesterol predicts periprocedural myocardial injury following percutaneous coronary intervention in poorly-controlled type 2 diabetes. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2016.12.010
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cardiologists. Before the procedure, all of the patients without contraindications received 100 mg of aspirin daily or a loading dose of 300 mg depending on whether they had already taken daily aspirin for at least 3 days, and they received 75 mg of clopidogrel daily or a loading dose of 300 mg depending on whether they had already taken clopidogrel for at least 3 days prior to intervention. All of the patients received either 5000 U or 70 U/kg bolus of unfractionated heparin just before the procedure and an additional bolus of 2000 to 3000 U were given every hour if the procedure lasted for more than an hour. Vascular access and PCI type (angioplasty only, angioplasty and stenting, or primary stenting) were determined by the interventional cardiologist according to the patient characteristics. Total balloon inflation times and inflation pressures were determined by the interventional cardiologist according to the technical properties of the balloon and the stent. After the procedure, all of the patients continued with aspirin and clopidogrel therapy daily. Use of glycoprotein IIb/ IIIa receptor antagonists or anticoagulants was at the discretion of the interventional cardiologist. Electrocardiogram monitoring All patients received a 12-lead electrocardiogram record before PCI, immediately after PCI, and in the case of symptoms that were interpreted as postprocedural ischemic events. All of the patients received continuous electrocardiogram monitoring using wireless technology after PCI during hospitalization. Biochemical measurements Fasting venous blood samples were obtained after at least a 12hour fast in the morning before intervention for measurement of fasting glucose levels, HbA1c, CK-MB activity, and the lipid profile. CTnI levels were determined in venous blood samples before PCI,
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24 hours after PCI, and in the event of symptoms or signs suggestive of myocardial ischemia. CTnI was analyzed using an immunochemiluminometric assay (Access AccuTnI, Beckman Coulter, Brea, CA, USA), the limit of detection was 0.01, and the total imprecision at the 99th percentile value was 14% [21]. The LDL-C concentration was analyzed using the selective solubilization method (1.006 < d < 1.063 g/ml, LDL test kit, Kyowa Medex, Tokyo, Japan). The HDL-C concentration was determined by a homogeneous method (Determiner HDL, Kyowa Medex). RC was calculated as TC minus HDL-C minus LDL-C, which reflected VLDL and chylomicrons in the present study. Plasma HbA1c and glucose levels were determined with conventional standard techniques. The ULN was defined as the 99th percentile of the normal population, with a total imprecision of <10%. The ULN of this test was 0.04 ng/ml. The peak cTnI value within 24 hours after the procedure was used for statistical analysis. Statistical analysis The data were presented as the mean SD, the median with interquartile ranges, or frequencies with percentages, as appropriate. Comparisons were made with independent-sample T tests, chisquare tests, Kruskal–Wallis tests, or Friedman tests as appropriate. Spearman rank correlation analyses were performed to determine the relationship between clinical parameters and postprocedural cTnI levels. Because plasma cTnI levels were not normally distributed, logtransformation was applied. Successful normalization of cTnI after log-transformation was evaluated using the Kolmogorov–Smirnov test. In logistic regression analyses, we used several multivariable models to examine the association of RC and RC/HDL-C levels with the occurrence of postprocedural cTnI elevation above various multiples of ULN in a hierarchical fashion. Specially, model 1 indicated the association with no adjustment for any confounding
Fig. 2. Adjusted impact of RC levels and RC/HDL ratio on postprocedural cTnI elevation in group B. RC, remnant cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; HbA1c, glycated hemoglobin; OR, odds ratio; cTnI, cardiac troponin I; ULN, upper limit of normal. Group B: HbA1c 7%, poorly controlled diabetes. Multivariate logistic regression model was adjusted for age, gender, body mass index, left ventricular ejection fraction, prior myocardial infarction, Gensini score, glucose, high-sensitivity C-reactive protein, intensity of statins, maximum inflation time, and number of postdilatations.
Please cite this article in press as: Zeng R-X, et al. Remnant cholesterol predicts periprocedural myocardial injury following percutaneous coronary intervention in poorly-controlled type 2 diabetes. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2016.12.010
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Table 1 Baseline clinical characteristics of the study population according to glycemic control. Group A (n = 563)
Variable Clinical characteristics Age, years Male, n (%) BMI, kg/m2 Hypertension, n (%) Dyslipidemia, n (%) Smoker, n (%) Family History of CAD, n (%) Unstable angina, n (%) LVEF, % Prior MI, n (%) Prior PCI, n (%) Prior CABG, n (%) TC, mg/dL LDL-C, mg/dL HDL-C, mg/dL NonHDL-C, mg/dL TC/HDL-C LDL-C/HDL-C NonHDL-C/HDL-C Triglyceride/HDL-C RC, mg/dL RC/HDL-C Triglyceride, mg/dL AIP HbA1c, % HbA1c, mmol/mol Glucose, mmol/L NT-proBNP, fmmol/L Creatinine, mmol/L Peak cTnI, ng/ml Hs-CRP, mg/L Hemoglobin, g/L Gensini score Prior treatment Statins, n (%)
Group B (n = 619)
p-value
60.16 9.50 401 (71.2) 26.30 3.03 410 (72.8) 479 (85.2) 307 (54.5) 133 (23.6)
58.88 9.05 437 (70.6) 26.70 3.28 431 (69.6) 514 (83.0) 328 (53.0) 127 (20.5)
0.018 0.848 0.029 0.247 0.339 0.598 0.206
300 (53.3) 64.02 6.60 37 (6.6) 165 (29.3) 22 (3.9) 154.45 38.64 90.88 31.81 40.25 9.39 114.20 36.62 3.97 1.14 2.34 0.89 2.97 1.14 4.09 2.81 23.32 14.24 0.63 0.46 136 (104–178) 0.54 0.25 6.43 0.39 46.82 4.25 5.91 1.19 529 (414–701) 77.01 16.66 0.06 (0.02–0.20) 1.56 (0.92–3.32) 139.12 14.87 32 (18–53)
300 (48.5) 63.05 6.73 62 (10.0) 172 (27.8) 17 (2.7) 163.40 42.09 96.27 33.25 39.81 10.20 123.59 39.91 4.26 1.21 2.50 0.89 3.26 1.21 4.87 4.23 27.31 22.14 0.75 0.68 142 (106–204) 0.59 0.27 8.24 1.15 66.56 12.53 7.76 2.38 538 (430–707) 75.25 15.27 0.05 (0.01–0.20) 1.98 (1.00–3.55) 140.34 14.63 37 (20–58)
556 (98.8)
609 (98.4)
0.917
Types Atorvastatin, n (%) Rosuvastatin, n (%) Simvastatin, n (%) Pravastatin, n (%) Fluvastatin, n (%) Pitavastatin, n (%)
299 67 137 25 11 17
(53.1) (11.9) (24.3) (4.4) (1.9) (3.0)
315 73 152 28 18 23
(50.9) (11.8) (24.6) (4.5) (2.9) (3.7)
0.224 0.975 0.889 0.701 0.311 0.476
Intensity of statins High-intensity, n (%) Moderate-intensity, n (%) Low-intensity, n (%) Aspirin, n (%) Clopidogrel, n (%) b-Blockers, n (%) Calcium blockers, n (%) ACE inhibitors, n (%) ARBs, n (%)
19 (3.4) 500 (88.8) 37 (6.6) 559 (99.3) 563 (100) 502 (89.2) 292 (52.0) 172 (30.6) 184 (32.7)
19 517 73 618 619 540 300 182 208
(3.1) (83.5) (11.8) (100) (100) (87.2) (48.5) (29.4) (33.6)
0.624 0.035 0.010 0.882 0.999 0.512 0.127 0.534 0.578
0.057 0.014 0.036 0.606 0.328 <0.001 0.004 0.435 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.003 <0.001 <0.001 <0.001 <0.001 0.538 0.059 0.144 0.015 0.157 0.034
Values are expressed as the mean SD, the median with interquartile range or n (%). Group A: HbA1c < 7%, well-controlled diabetes; Group B: HbA1c 7%, poorly controlled diabetes. The bold values indicate p < 0.05. High-intensity of statins was patients with atorvastatin 40 mg to 80 mg, or resuvastatin 20 mg to 40 mg; Moderate-intensity therapy was patients daily with atorvastatin 10 mg to 20 mg, or resuvastatin 5 mg to 10 mg, or simvastatin 20 mg to 40 mg; or pravastatin 40 mg to 80 mg; or fluvastatin 80 mg, or pitavastatin 2 mg to 4 mg; Low-intensity therapy was patients with simvastatin 10 mg; or pravastatin 10 mg to 20 mg; or fluvastatin 20 mg to 40 mg, or pitavastatin 1 mg. BMI, body mass index; CAD, coronary artery disease; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; TC, Total Cholesterol; LDL-C, low-density lipoprotein cholesterol; RC, remnant cholesterol; HDL-C, high-density lipoprotein cholesterol; AIP, atherogenic index of plasma; HbA1c, glycated hemoglobin; NTpro-BNP, N-terminal pro-brain natriuretic peptide; CTnI, cardiac troponin I; HsCRP, high-sensitivity C-reactive protein; ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers.
factors, model 2 was with the adjustment for the conventional risk factors such as age and gender, and model 3 was designed to adjust for the conventional risk factors plus the variables that were significantly associated with postprocedural cTnI in the present population with a p-value <0.05. Besides, the multivariable models to examine the association of RC and RC/HDL-C tertiles (Fig. 2) were the same as model 3. A 2-tailed p-value of <0.05 was considered to be statistically significant. All of the analyses were performed using SPSS version 19.0 software (Chicago, IL, USA).
Results Baseline and procedural characteristics Finally, 1182 patients were included in this analysis. Table 1 demonstrates the baseline clinical characteristics of diabetic patients according to the control status of diabetes. Group A (n = 563) was defined as patients with HbA1c <7%, well-controlled diabetes; Group B (n = 619) was characterized as HbA1c 7%, poorly-controlled diabetes. As shown in Table 1, when compared to group B, patients in group A were older with a lighter weight (both p < 0.05). Moreover, patients in group A had less prior MI, lower high-sensitivity C-reactive protein levels, Gensini score (the coronary extent scoring system), but higher left ventricular ejection fraction (LVEF) than those in group B (all p < 0.05). Table 2 shows the procedural characteristics. Patients in group A had more maximum inflation time and received fewer balloons postdilatation (both p < 0.05). However, no significant differences were observed in vascular access, target vessels, target lesion sites, bifurcation lesions, in-stent restenosis, kissing balloon use, target lesion types, stent numbers, total stent lengths, predilation times, maximum inflation pressure, and maximum inflation times among the two groups (all p > 0.05). Table 2 Procedural characteristics of the study population according to glycemic control. Procedural characteristics Transradial access, n (%) Target vessel Left main Left anterior descending Left circumflex Right coronary artery Grafts Lesion location Proximal Middle Distal Branch Lesion classification ACC/AHA type A/B1 ACC/AHA type B2/C Final TIMI III flow, n (%) Bifurcation lesions, n (%) Use of kissing balloon, n (%) Occlusion lesions, n (%) In-stent restenosis, n (%) Number of stents implanted Total stent length, mm Maximum pressure, atm Maximum inflation time, s Number of predilations Number of postdilatations
Group A (n = 563)
Group B (n = 619)
p-value
502 (89.2)
559 (90.3)
0.565
29 317 183 215 3
(5.2) (56.3) (32.5) (38.2) (0.5)
24 353 201 238 1
(3.9) (57.0) (32.5) (38.4) (0.2)
0.326 0.814 0.999 0.952 0.352
286 358 166 139
(50.8) (63.6) (29.5) (24.7)
344 402 173 165
(55.6) (64.9) (28.1) (26.7)
0.199 0.476 0.869 0.883
165 (26.8) 491 (79.3) 601 (97.1) 232 (37.5) 51 (8.2) 94 (14.9) 24 (3.9) 1.97 1.02 43.98 27.04 17.75 3.53 9.62 3.57 3.0 (1.0–5.0) 4.0 (3.0–7.0)
0.449 0.195 0.894 0.933 0.666 0.505 0.724 0.891 0.542 0.701 0.011 0.186 0.038
164 (29.2) 437 (77.8) 553 (98.2) 213 (37.9) 42 (7.5) 74 (13.1) 27 (4.8) 1.96 1.05 43.03 26.38 17.84 3.80 10.21 4.39 2.0 (1.0–5.0) 4.0 (2.0–6.0)
Values are expressed as the mean SD, the median with interquartile range or n (%). Group A: HbA1c < 7%, well-controlled diabetes; Group B: HbA1c 7%, poorly controlled diabetes. The bold values indicate p < 0.05. ACC, American College of Cardiology; AHA, American Heart Association; TIMI, thrombolysis in myocardial infarction.
Please cite this article in press as: Zeng R-X, et al. Remnant cholesterol predicts periprocedural myocardial injury following percutaneous coronary intervention in poorly-controlled type 2 diabetes. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2016.12.010
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and RC/HDL-C levels had higher postprocedural cTnI levels (r = 0.099, p = 0.014 and r = 0.109, p = 0.007, respectively).
Lipid parameters and PMI As shown in Table 1, the levels of TC, LDL-C, nonHDL-C, triglyceride, AIP, RC and RC/HDL-C, TC/HDL-C, LDL-C/HDL-C, nonHDL-C/HDL-C, and triglyceride/HDL-C were significantly different between group A and B (p < 0.05). The associations of lipid parameters with PMI were investigated respectively on the basis of the glycemic control status (Table 3). Interestingly, the associations of lipid parameters with PMI were presented differently between patients with well-controlled diabetes and patients with poorly-controlled diabetes (Table 3). In group A, that was the group of well-controlled diabetes, except for the AIP and triglyceride (p < 0.05), the lipid parameters including RC, RC/HDL-C, TC/HDL-C, LDL-C/HDL-C, nonHDL-C/HDL-C, and triglyceride/HDL-C showed no significant association with PMI (all p > 0.05). The LVEF were also not different between the four groups divided by PMI (p > 0.05). In group B, that was the group of poorly-controlled diabetes, however, the lipid parameters including RC, RC/HDL-C, AIP, TC/HDL-C, nonHDL-C/HDL-C, and triglyceride/HDL-C were significantly and positively related to PMI (all p < 0.05). Moreover, the data from Spearman rank correlation analyses (not shown in the Table) consistently revealed that both RC and RC/ HDL-C levels had no association with postprocedural cTnI levels in group A, while in group B, patients with higher preprocedural RC
Logistic regression analysis In a univariate logistic regression analysis, we determined that RC (per 1-SD increase) and RC/HDL-C were significantly associated with a greater risk of postprocedural cTnI elevation above 3 ULN and 5 ULN in group B, but not in group A (Table 4, Model 1). After adjustment for age and gender, we found a similar result to the unadjustment model (Table 4, Model 2). Meanwhile, we further determined the independent associations between RC or RC/HDL-C and the development of postprocedural cTnI elevation. As a result, in group B, a 1-SD increase in RC produced 30% and 32% increased risk of postprocedural cTnI >3 ULN and >5 ULN, respectively, but not in group A. Importantly, the causal odds ratio (OR) for RC/ HDL-C was 1.43 [95% confidence interval (CI): 1.10 to 1.88) and 1.49 (95% CI: 1.13 to 1.97) in group B with postprocedural cTnI >3 ULN and >5 ULN, respectively, presenting the highest values when compared to the other cholesterol fractions including TC/ HDL-C, LDL-C/HDL-C, nonHDL-C/HDL-C, and triglyceride/HDL-C (Table 4, Model 3). Furthermore, in a multivariate logistic regression model, patients with RC levels >27.46 mg/dL (third tertile) compared with RC levels 14.15 mg/dL (first tertile) were associated with a
Table 3 Parameters in group A and group B according to postprocedural cTnI elevation. Variable Group A n (%) TC, mg/dL LDL-C, mg/dL HDL-C, mg/dL RC, mg/dL NonHDL-C, mg/dL RC/HDL-C TC/HDL-C LDL-C/HDL-C NonHDL-C/HDL-C Triglyceride/HDL-C Triglyceride, mg/dL HbA1c, % NT-proBNP, fmmol/L AIP Gensini score LVEF, % TIMI III, n (%) Group B n (%) TC, mg/dL LDL-C, mg/dL HDL-C, mg/dL RC, mg/dL NonHDL-C, mg/dL RC/HDL-C TC/HDL-C LDL-C/HDL-C NonHDL-C/HDL-C Triglyceride/HDL-C Triglyceride, mg/dL HbA1c, % NT-proBNP, fmmol/L AIP Gensini score LVEF, % TIMI III, n (%)
cTnI elevation 1 ULN
1 ULN < cTnI elevation 3 ULN
3 ULN < cTnI elevation 5 ULN
cTnI elevation > 5 ULN
240 (42.6) 153.24 38.00 89.44 30.98 39.34 8.85 24.46 16.98 113.91 36.29 0.68 0.55 4.04 1.19 2.35 0.91 3.04 1.19 4.56 3.49 148 (106–185) 6.44 0.37 514 (402–637) 0.58 0.26 20 (4–40) 63.89 6.73 237 (97.5)
117 (20.8) 151.16 34.47 88.11 28.84 41.12 10.12 21.93 10.00 110.04 31.18 0.59 0.34 3.80 0.95 2.22 0.76 2.80 0.95 3.60 2.03 122 (102–159) 6.43 0.39 550 (440–757) 0.50 0.23 20 (5–47) 64.77 6.93 115 (98.2)
63 (11.2) 160.03 41.94 95.66 34.86 39.57 7.99 24.80 13.57 120.46 39.75 0.66 0.37 4.13 1.11 2.47 0.95 3.13 1.11 4.03 2.17 144 (105–186) 6.49 0.36 526 (398–647) 0.55 0.21 24 (4–45) 64.12 5.05 62 (98.4)
143 (25.4) 154.45 38.64 93.45 33.95 41.39 10.09 21.89 12.20 115.34 39.66 0.58 0.38 3.94 1.19 2.35 0.95 2.94 1.19 3.73 2.17 123 (99–170) 6.40 0.43 557 (429–749) 0.50 0.25 26 (6–50) 63.55 6.73 139 (97.2)
0.409 0.293 0.126 0.189 0.320 0.116 0.206 0.307 0.206 0.060 0.017 0.464 0.051 0.009 0.531 0.511 0.741
290 (46.8) 158.55 40.61 93.42 32.65 40.34 9.50 24.80 17.16 118.22 38.35 0.67 0.57 4.05 1.14 2.39 0.85 3.05 1.14 4.43 3.62 135 (103–194) 8.31 1.22 513 (425–650) 0.56 0.26 20 (4–45) 63.27 7.29 284 (97.9)
129 (20.8) 165.46 45.34 98.70 36.27 39.24 12.06 27.52 25.94 126.22 43.21 0.80 0.82 4.44 1.41 2.64 1.02 3.44 1.41 4.93 3.84 146 (107–205) 8.25 1.12 545 (446–709) 0.60 0.28 28 (6–47) 62.14 5.86 125 (96.9)
44 (7.1) 169.16 38.74 99.87 34.28 40.99 8.91 28.30 27.22 128.17 38.51 0.76 0.82 4.28 1.20 2.52 0.95 3.28 1.20 5.02 5.98 138 (107–201) 8.02 0.96 508 (428–804) 0.57 0.30 23 (7–58) 63.58 5.84 42 (95.5)
156 (25.2) 169.07 42.25 98.56 31.31 38.97 10.14 31.54 24.77 130.10 39.33 0.87 0.69 4.48 1.14 2.61 0.81 3.48 1.14 5.61 4.91 155 (109–233) 8.17 1.08 572 (431–821) 0.644 0.29 32 (8–52) 63.26 6.53 150 (96.1)
0.050 0.253 0.421 0.023 0.014 0.021 0.001 0.015 0.001 0.044 0.069 0.378 0.036 0.019 0.043 0.392 0.649
p-value
Group A: HbA1c < 7%, well-controlled diabetes; Group B: HbA1c 7%, poorly controlled diabetes. The bold values indicate p < 0.05. TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; RC, remnant cholesterol; HDL-C, high-density lipoprotein cholesterol; HbA1c, glycated hemoglobin; NTpro-BNP, N-terminal pro-brain natriuretic peptide; CTnI, cardiac troponin I; ULN, upper limit of normal; AIP, atherogenic index of plasma; LVEF, left ventricular ejection fraction; TIMI, thrombolysis in myocardial infarction.
Please cite this article in press as: Zeng R-X, et al. Remnant cholesterol predicts periprocedural myocardial injury following percutaneous coronary intervention in poorly-controlled type 2 diabetes. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2016.12.010
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JJCC-1447; No. of Pages 8 R.-X. Zeng et al. / Journal of Cardiology xxx (2016) xxx–xxx
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Table 4 Logistic regression analysis of RC and RC/HDL-C for postprocedural cTnI elevation in group A and group B. Group A
Variable
Model 1 RC (per 1-SD increase) RC/HDL-C TC/HDL-C LDL-C/HDL-C NonHDL-C/HDL-C Triglyceride (per 10 mg/dL increase) Triglyceride/HDL-C Model 2 RC (per 1-SD increase) RC/HDL-C TC/HDL-C LDL-C/HDL-C NonHDL-C/HDL-C Triglyceride (per 10 mg/dL increase) Triglyceride/HDL-C Model 3 RC (per 1-SD increase) RC/HDL-C TC/HDL-C LDL-C/HDL-C NonHDL-C/HDL-C Triglyceride (per 10 mg/dL increase) Triglyceride/HDL-C
Group B
cTnI elevation > 3 ULN
cTnI elevation > 5 ULN
cTnI elevation > 3 ULN
cTnI elevation > 5 ULN
OR (95% CI)
OR (95% CI)
OR (95% CI)
OR (95% CI)
p-value
p-value
p-value
p-value
0.94 0.79 1.03 1.10 1.03 0.99 0.94
(0.79–1.12) (0.53–1.18) (0.88–1.19) (0.91–1.34) (0.88–1.19) (0.97–1.01) (0.88–1.01)
0.496 0.247 0.728 0.301 0.728 0.189 0.095
0.86 0.68 0.96 1.03 0.96 0.98 0.93
(0.69–1.06) (0.43–1.10) (0.81–1.14) (0.83–1.27) (0.81–1.14) (0.96–1.01) (0.86–1.01)
0.166 0.118 0.658 0.811 0.658 0.142 0.083
1.25 1.33 1.19 1.17 1.19 1.02 1.05
(1.06–1.48) (1.04–1.70) (1.04–1.37) (0.97–1.41) (1.04–1.37) (1.00–1.03) (1.01–1.09)
0.010 0.022 0.012 0.108 0.012 0.009 0.017
1.25 1.36 1.21 1.19 1.21 1.02 1.05
(1.06–1.49) (1.06–1.74) (1.05–1.41) (0.97–1.45) (1.05–1.41) (1.00–1.03) (1.01–1.09)
0.010 0.017 0.009 0.094 0.009 0.010 0.015
0.97 0.83 1.06 1.14 1.06 1.02 0.95
(0.81–1.16) (0.55–1.26) (0.90–1.23) (0.94–1.38) (0.90–1.23) (1.00–1.04) (0.89–1.02)
0.703 0.382 0.488 0.193 0.488 0.132 0.172
0.89 0.73 1.00 1.06 1.00 1.02 0.94
(0.71–1.09) (0.45–1.20) (0.84–1.19) (0.86–1.32) (0.84–1.19) (1.00–1.05) (0.87–1.02)
0.295 0.211 0.958 0.581 0.958 0.057 0.171
1.29 1.43 1.25 1.21 1.25 1.03 1.06
(1.09–1.53) (1.11–1.84) (1.08–1.44) (1.00–1.47) (1.08–1.44) (1.01–1.05) (1.02–1.11)
0.004 0.006 0.002 0.045 0.002 0.009 0.003
1.31 1.48 1.28 1.24 1.28 1.04 1.07
(1.10–1.56) (1.14–1.91) (1.10–1.49) (1.01–1.52) (1.10–1.49) (1.01–1.06) (1.02–1.11)
0.003 0.003 0.001 0.040 0.001 0.002 0.002
0.94 0.79 1.04 1.13 1.04 0.99 0.95
(0.78–1.14) (0.52–1.22) (0.88–1.24) (0.92–1.40) (0.88–1.24) (0.97–1.01) (0.88–1.02)
0.523 0.287 0.624 0.243 0.624 0.253 0.143
0.86 0.68 0.96 1.03 0.96 0.99 0.94
(0.68–1.08) (0.41–1.15) (0.79–1.16) (0.81–1.30) (0.79–1.16) (0.96–1.01) (0.87–1.03)
0.191 0.148 0.658 0.828 0.957 0.271 0.174
1.30 1.43 1.27 1.24 1.27 1.02 1.06
(1.08–1.56) (1.10–1.88) (1.09–1.47) (1.01–1.52) (1.09–1.47) (1.01–1.03) (1.02–1.11)
0.007 0.009 0.002 0.041 0.002 0.008 0.008
1.32 1.49 1.30 1.27 1.30 1.02 1.07
(1.09–1.60) (1.13–1.97) (1.11–1.54) (1.02–1.58) (1.11–1.54) (1.01–1.04) (1.02–1.12)
0.004 0.005 0.001 0.033 0.001 0.005 0.004
RC, remnant cholesterol; HDL-C, high-density lipoprotein cholesterol; HbA1c, glycated hemoglobin; LDL-C, low-density lipoprotein cholesterol; OR, odds ratio; CTnI, cardiac troponin I; ULN, upper limit of normal; BMI body mass index; LVEF, left ventricular ejection fraction; MI, myocardial infarction; hs-CRP, high-sensitivity C-reactive protein. Group A: HbA1c < 7%, well-controlled diabetes; SDs were 14.24 mg/dL for RC; Group B: HbA1c 7%, poorly-controlled diabetes; SDs were 22.14 mg/dL for RC; Model 1: no adjustment; Model 2: adjusted for age and gender; Model 3: adjusted for model 2+ BMI, LVEF, prior MI, Gensini score, glucose, hs-CRP, intensity of statins, maximum inflation time, number of postdilatations.
1.57-fold and 2-fold increased risk of postprocedural cTnI >3 ULN and >5 ULN in group B, respectively (Fig. 2). In addition, patients with RC/HDL-C ratio >0.74 (third tertile) compared with RC/HDL-C ratio 0.46 (first tertile) were associated with a 2.18fold and 2.65-fold increased risk of postprocedural cTnI >3 ULN and >5 ULN in group B, respectively (Fig. 2). Discussion In this study of patients with T2D undergoing PCI, we firstly investigated the effect of RC and RC/HDL-C on the risk of PMI. The main findings were as follows: (1) There were significant differences in levels of RC and RC/HDL-C between patients with well-controlled diabetes and poorly-controlled diabetes; (2) The associations of RC and RC/HDL-C with PMI could be observed in patients with poorly-controlled diabetes but not in the wellcontrolled group; (3) A 1-SD increase in RC produced 30% and 32% increased risk for postprocedural cTnI >3 ULN and >5 ULN, respectively, while the causal ORs were 1.43 (95% CI: 1.10 to 1.88) and 1.49 (95% CI: 1.13 to 1.97) for RC/HDL-C in poorly-controlled diabetes; Patients with RC levels >27.46 mg/dL (third tertile) compared with RC levels 14.15 mg/dL (first tertile) had a 1.57fold and 2-fold increased risk for postprocedural cTnI >3 ULN and >5 ULN in poorly-controlled diabetes, respectively; (4) Compared to the cholesterol fractions including TC/HDL-C, LDL-C/HDLC, nonHDL-C/HDL-C, and triglyceride/HDL-C, the predictive values of RC/HDL-C measured by the ORs for PMI seemed to be the highest. Therefore, these findings might indicate the different benefit to gain by reducing levels of RC in T2D between wellcontrolled and poorly-controlled groups, suggesting the clinical implications with the role of RC in the development and outcomes of diabetic patients with PCI and the need for large clinical
intervention trials examining if lowering of RC in individuals with elevated levels will reduce cardiovascular risk in diabetic populations. To date, risk factors for PMI can broadly be categorized as patient-related, lesion-related, and procedure-related [22]. However, the definite risk stratification of PMI following PCI remains uncertain. So our team paid more attention to the study about PMI, and previously demonstrated that nonHDL-C compared to LDL-C was a better predictor for PMI in poorly-controlled patients with T2D, and that increased preprocedural N-term pro-B-type natriuretic peptide (NT-pro-BNP) levels were strongly and independently associated with the higher risk of PMI [23,24]. Furthermore, several studies reported that remnant lipoproteins were associated with increased risk for cardiovascular disease [8,9,25–30]. A study from Varbo et al. [8] suggested that elevated levels of RC and increased ratio of RC to HDL-C were associated with increased risk of ischemic heart disease in the general population. In this study, for the further convenience of risk stratification of PMI related to PCI, we firstly revealed the associations between RC levels, RC/HDL-C ratio or other lipid profiles ratio, and PMI following PCI in poorly-controlled diabetic patients, might provide one of the mechanisms of adverse outcomes following PCI in poorly-controlled diabetics, which differed from our previous study. It has been well established that T2D is associated with varied lipid abnormalities, including increased remnant lipoproteins, which may cause macrovascular complications [31–33]. RC is the cholesterol content of triglyceride-rich lipoproteins, and is higher in diabetic patients with CAD [31,34]. Triglyceride-rich lipoproteins are of particular importance in diabetic populations because insulin resistance increases hepatic VLDL production and decreases clearance of triglyceride-rich lipoproteins [35]. In the
Please cite this article in press as: Zeng R-X, et al. Remnant cholesterol predicts periprocedural myocardial injury following percutaneous coronary intervention in poorly-controlled type 2 diabetes. J Cardiol (2017), http://dx.doi.org/10.1016/j.jjcc.2016.12.010
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present study, the majority of RC were VLDL and chylomicron remnants. the Penn Diabetes Heart Study reported that VLDLcholesterol was associated with coronary artery calcification independent of established cardiovascular risk factors [35]. Moreover, one study indicated that high levels of remnant-like lipoprotein particles cholesterol had a crucial role in the pathogenesis of CAD in T2D, and remnant lipoproteinemia represented a risk factor that should be a therapeutic target in diabetic patients [29]. However, we found the association of both RC and RC/HDL-C levels with increased PMI risk in poorlycontrolled diabetes but not well-controlled diabetes. Although the exact mechanism was unclear, the potential reason for explaining the disparity might be related to the glycemic control. A study reported that improved glycemic control could promote lipid homeostasis in T2D by lowering triglyceride levels and causing a favorable change in HDL and LDL composition [36]. Thus, the findings of the present study might also point out the importance of glycemic control in diabetic patients who underwent PCI. To our knowledge, the definite explanations for a causal effect of elevated RC on PMI in poorly-controlled T2D are unclear. However, previous studies might give certain clues. For example, research reported that remnant-like lipoprotein particle cholesterol increases production of tissue factor, which is essential for the thrombotic events in endothelial cells [29,37] and enhances aggregation of platelets [38]. In addition, one study demonstrated the causal association of non-fasting RC with low-grade inflammation, which may be involved in atherogenesis [39], a disease with a known inflammatory nature [40]. Some limitations existed in this study. First, the cardiovascular events were not analyzed due to cross-sectional features of the study. Moreover, although we adjusted the multivariable analysis for factors that influence postprocedural cTnI levels, residual confounders and hidden comorbidities on PMI might have been not entirely eliminated. The analysis would be more valuable if it were done separately on all the available 24 h troponin values and on the incidence of periprocedural symptoms of ischemia and signs (including absolute troponin values measured in this subset). Besides, the present study lacked enough information regarding diabetes: such as, duration, microvascular complications, and treatment. Finally, there were different methods to assay for measuring remnant lipoproteins [29,41]. Our study used the calculation method [8,39], which might be not as precise as directly measuring remnants. Conclusion In conclusion, in poorly-controlled diabetic patients undergoing PCI, RC as well as RC/HDL-C might be independent predictors for PMI. Conversely, neither RC nor RC/HDL-C levels were associated with PMI in well-controlled diabetic patients. Funding This work was partially supported by the National Natural Scientific Foundation (81070171, 81241121), the Specialized Research Fund for the Doctoral Program of the Higher Education of China (20111106110013), the Capital Special Foundation of Clinical Application Research (Z121107001012015), the Capital Health Development Fund (2011400302), and the Beijing Natural Science Foundation (7131014) awarded to Dr Jian-Jun Li, MD, PhD. Conflicts of interest The authors have no conflicts of interest to disclose.
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