Abstract
Aim: This study aimed to investigate the association between a combination of elevated triglyceride (TG) and reduced high-density lipoprotein cholesterol (HDL-C) levels and target lesion revascularization (TLR) following everolimus-eluting stent (EES) implantation. The adverse impact of clinical, lesion, and procedural characteristics on TLR in patients with elevated TG and reduced HDL-C levels was also assessed.
Methods: We retrospectively collected data on 3,014 lesions from 2,022 consecutive patients, who underwent EES implantation at Koto Memorial Hospital. Atherogenic dyslipidemia (AD) is defined as a combination of non-fasting serum TG ≥ 175 mg/dL and HDL-C ＜40 mg/dL.
Results: AD was observed in 212 lesions in 139 (6.9%) patients. The cumulative incidence of clinically driven TLR was significantly higher in patients with AD than in those without AD (hazard ratio [HR] 2.31, 95% confidence interval [CI] 1.43–3.73,P=0.0006). Subgroup analysis showed that AD increased the risk of TLR with the implantation of small stents (≤ 2.75 mm). Multivariable Cox regression analysis showed that AD was an independent predictor of TLR in the small EES stratum (adjusted HR 3.00, 95% CI 1.53–5.93,P=0.004), whereas the incidence of TLR was similar in the non-small-EES stratum, irrespective of the presence or absence of AD.
Conclusions: Patients with AD had a higher risk of TLR after EES implantation, and this risk was greater for lesions treated with small stents.
Keywords: Atherogenic dyslipidemia, Drug-eluting stent, Restenosis, Percutaneous coronary intervention
See editorial vol. 30: 1761-1762
Introduction
New second-generation drug-eluting stents (DESs) decreased the incidence of restenosis within 1 year compared with bare metal stents (BMSs) and overcame stent thrombosis, as it is often seen with the first-generation DES 1) . Everolimus-eluting stents (EESs) are the most widely used second-generation DES worldwide, with favorable long-term results in recent decades 2 , 3) . The development of percutaneous coronary intervention (PCI) techniques and imaging devices has also reduced the rate of stent failure. However, target lesion revascularization (TLR) tends to exist after EES implantation and continues beyond one year 4 , 5) . Because DES-TLR treatment is more complex and associated with a worse prognosis than revascularization of de novo lesions, it is important to reveal the risk factors of TLR after EES implantation.
Atherogenic dyslipidemia (AD) is characterized by elevated serum triglyceride (TG) and reduced high-density lipoprotein cholesterol (HDL-C) 6 - 8) . Previous studies have indicated that AD is associated with worse clinical outcomes after the implantation of BMS and first-generation DES 9 , 10) . However, the impact of AD on TLR after the implantation of newer, second-generation DES remains unknown. Furthermore, there is a lack of data on the clinical characteristics of risk stratification in AD patients undergoing PCI. In this study, we investigated whether AD, following EES implantation, contributes to clinically driven TLR. We also aimed to determine whether clinical, lesion, or procedural characteristics could predict the influence of AD on the prevalence of TLR.
Aim
We aimed to assess the correlation between AD and TLR in the newer DES era and determine the specific subgroup that had adverse effects on TLR in AD patients.
Methods
Study Population
This was a retrospective cohort study of 2,049 consecutive patients who underwent PCI with EES at Koto Memorial Hospital, from February 2010 to June 2017. We evaluated the procedures performed on each patient within 3 months of the initial PCI. We excluded 16 patients with in-hospital death, 3 with subacute stent thrombosis, and 8 with inadequate laboratory data. The remaining 2,022 patients with 3,014 lesions were included in the present analysis and divided into two groups according to the presence of AD during the initial procedure; there were 1,883 non-AD patients with 2,802 lesions and 139 AD patients with 212 lesions. AD was defined as a ≥ 175 mg/dL non-fasting TG level and ＜40 mg/dL HDL-C level. The flowchart of the study is shown in Fig.1 .
Fig.1. Study flow chart.
EES, everolimus-eluting stent; PCI, percutaneous coronary intervention; SAT, subacute stent thrombosis.
This study was conducted by the Declaration of Helsinki, and the Institutional Ethics Committee of the Koto Memorial Hospital approved the study protocol. Due to the retrospective design of the study, consent was obtained from all participants through an opt-out methodology.
Data Collection and Follow-Up
Demographic, clinical, angiographic, procedural, and outcome data were collected from the hospital records or electronic databases at our hospital. Lesion complexity was categorized according to the American College of Cardiology (ACC) or American Heart Association (AHA) classification. Follow-up information was obtained from hospital charts or by contacting the patients, their relatives, or the referring physicians. Follow-up coronary angiography or computed tomography was not planned routinely but was performed at the discretion of the referring physicians.
Clinical Outcomes and Definitions
The primary outcome in the study was that the clinically driven TLR assessed up to an 8-year follow-up interval after EES implantation; it was defined as a repeat PCI or coronary artery bypass grafting due to restenosis of the target lesion associated with recurrent angina and/or evidence of myocardial ischemia. All-cause death, cardiovascular death, myocardial infarction, and target vessel revascularization (TVR) were also assessed as endpoints.
Subgroup Analysis
Subgroup analyses were conducted for each demographic, clinical, angiographic, and procedural finding, and the interactions in the Cox proportional hazards models were also examined. As we also sought to evaluate the association between the incidence of TLR and the presence of AD according to the size of the implanted stent, the lesions were divided into two strata: small stent use and no-small stent use; small stent use included at least one stent with a size of ≤ 2.75 mm; A total of 1,183 (39.3%) and 1,831 (60.7%) lesions were treated with and without small stents, respectively.
Statistical Analysis
Categorical variables were reported as numbers and percentages and compared using the chi-square or Fisher’s exact test. Continuous variables with normal distribution were expressed as mean±standard deviation and compared using the Student’s t-test. Continuous variables with non-normal distribution were expressed as medians and interquartile ranges and compared using the Wilcoxon rank-sum test. The cumulative incidence was estimated using the Kaplan–Meier method, and differences were assessed using the log-rank test. We also performed a subgroup analysis to investigate the effect of demographic, clinical, angiographic, and procedural factors on the influence of AD. A Cox proportional hazard model was used to identify the independent risk factors for TLR in the small stent use stratum. Based on the results of the univariable analysis and previous reports, the Cox multivariable regression analysis included the following variables: age, sex, diabetes mellitus, AD, statin use, in-stent restenosis (ISR) lesion, and total stent length 11 , 12) . Model 1 included age, sex, and the significant factors in univariable analysis; in model 2, diabetes mellitus was added to the covariates of model 1.
The level of statistical significance was set at P＜0.05. All data were analyzed using the JMP version 16.0 software (SAS Institute, Inc., Cary, NC, USA).
Results
Patient, Lesion, and Procedural Characteristics
Tables 1 and 2 show the summary of baseline clinical characteristics. The mean age of the entire study population was 71.8±10.1 out of which 73% were male and 6.9% had AD. Compared with the non-AD group, the AD group included younger age, more males, and higher body mass index (BMI); the prevalence of smoking behavior, family history of ischemic heart disease, and history of PCI were significantly higher in patients with AD. Low-density lipoprotein (LDL) cholesterol and HbA1c levels and medication at PCI were comparable between the two groups. The prevalence of type B2/C, ISR, and chronic total occlusion lesions was higher in the AD group than in the non-AD group.
Table 1. Clinical characteristics.
| Overall (n = 2,022) | Non-AD (n = 1,883) | AD (n = 139) | P-value | |
|---|---|---|---|---|
| Age, years | 71.8±10.1 | 72.1±10.0 | 67.0±10.5 | ＜0.0001 |
| Male | 1,475 (73) | 1,348 (72) | 127 (91) | ＜0.0001 |
| Body mass index, kg/m2 | 24.0±3.5 | 23.9±3.5 | 25.2±2.8 | ＜0.0001 |
| Risk factor | ||||
| Hypertension | 1,534 (76) | 1,402 (75) | 112 (81) | 0.17 |
| Chronic kidney disease | 971 (48) | 907 (48) | 64 (46) | 0.63 |
| Hemodialysis | 25 (1) | 23 (1) | 2 (1) | 0.69 |
| Smoking | 558 (28) | 487 (26) | 66 (47) | ＜0.0001 |
| Family history of IHD | 246 (12) | 219 (12) | 25 (18) | 0.03 |
| Previous MI | 328 (16) | 298 (16) | 30 (22) | 0.09 |
| Previous PCI | 805 (40) | 737 (39) | 68 (49) | 0.02 |
| Previous CABG | 33 (2) | 31 (2) | 2 (1) | 1.00 |
| Laboratory findings | ||||
| Triglycerides, mg/dL | 125 [91-183] | 120 [88-167] | 241 [204-320] | ＜0.0001 |
| LDL-C, mg/dL | 107.7±30.7 | 107.9±31.1 | 104.5±24.8 | 0.22 |
| HDL-C, mg/dL | 50.5±13.8 | 51.7±13.5 | 34.1±4.3 | ＜0.0001 |
| HbA1c, % | 6.2±1.0 | 6.2±1.0 | 6.3±1.2 | 0.08 |
| eGFR, mL/min/1.73m2 | 61.4±21.3 | 61.3±21.6 | 62.5±17.3 | 0.53 |
| BNP, pg/mL | 34 [16-88] | 35 [16-91] | 25 [10-52] | ＜0.0001 |
| TG/HDL-C ratio | 3.4±2.7 | 2.8±1.7 | 8.5±3.8 | ＜0.0001 |
| Medication at PCI | ||||
| Aspirin | 1,998 (99) | 1,861 (99) | 137 (99) | 0.69 |
| Thienopyridine | 1,948 (96) | 1,810 (97) | 138 (99) | 0.17 |
| Statin | 1,387 (69) | 1,298 (69) | 89 (64) | 0.23 |
| ACEI/ARB | 1,243 (61) | 1,157 (61) | 86 (62) | 0.92 |
| Beta blocker | 460 (23) | 427 (23) | 33 (24) | 0.79 |
| MRA | 231 (11) | 218 (12) | 13 (9) | 0.41 |
Data are presented as the mean±SD, median [interquartile range], or number (%). ACEI, angiotensin-converting enzyme inhibitor; AD, atherogenic dyslipidemia; ARB, angiotensin receptor blocker; BNP, B-type natriuretic peptide; CABG, coronary artery bypass grafting; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; IHD, ischemic heart disease; LDL-C, low-density lipoprotein cholesterol; MRA, mineralocorticoid receptor antagonist; MI, myocardial infarction; PCI, percutaneous coronary intervention; TG, triglyceride.
Table 2. Lesion and procedural characteristics.
| Overall (n = 3,014) | Non-AD (n = 2,802) | AD (n = 212) | P-value | |
|---|---|---|---|---|
| ACS | 461 (15) | 431 (15) | 30 (14) | 0.63 |
| Target vessel | 0.0006 | |||
| LMCA | 123 (4) | 107 (4) | 16 (8) | |
| LAD | 1,233 (41) | 1,166 (42) | 67 (32) | |
| LCx | 767 (25) | 718 (26) | 49 (23) | |
| RCA | 891 (30) | 811 (29) | 80 (38) | |
| Lesion type | ||||
| ACC/AHA type B2/C | 2,520 (84) | 2,239 (83) | 191 (90) | 0.008 |
| ISR lesion | 228 (8) | 202 (7) | 26 (12) | 0.007 |
| True bifurcation | 1,003 (33) | 932 (33) | 71 (33) | 0.95 |
| Calcified lesion | 1,824 (61) | 1,693 (60) | 141 (67) | 0.08 |
| Aorto-ostial lesion | 142 (5) | 128 (5) | 14 (7) | 0.18 |
| CTO | 107 (4) | 93 (3) | 14 (7) | 0.01 |
| Number of stents | 1.28±0.57 | 1.28±0.56 | 1.35±0.67 | 0.10 |
| Stent diameter, mm | 3 [2.5-3.5] | 3 [2.5-3.5] | 3 [2.5-3.5] | 0.09 |
| 2.97±0.44 | 2.96±0.42 | 3.02±0.41 | ||
| Small stent use (≤ 2.75 mm) | 1,181 (39) | 1,113 (40) | 68 (32) | 0.03 |
| Total stent length, mm | 23 [15-35] | 23 [15-33] | 23 [15-38] | 0.30 |
| 29.3±18.6 | 29.2±18.4 | 30.6±21.1 | ||
| Total stent length ＞28 mm | 954 (32) | 888 (32) | 66 (31) | 0.87 |
| Use of imaging devices | 3,008 (99.8) | 2,796 (99.8) | 212 (100) | 0.50 |
| IVUS | 3,003 (99.8) | 2,792 (99.9) | 212 (100) | 0.58 |
| Minimum stent area, mm2 | 5.8±2.3 | 5.8±2.3 | 6.0±2.3 | 0.22 |
| Minimum stent area ＜5.4 mm2 | 1,418 (48) | 1,332 (49) | 86 (42) | 0.04 |
Data are presented as the mean±SD, median [interquartile range], or number (%). ACC, American College of Cardiology; ACS, acute coronary syndrome; AD, atherogenic dyslipidemia; AHA, American Heart Association; CTO, chronic total occlusion; ISR, in-stent restenosis; IVUS, intravascular ultrasound; LAD, left anterior descending coronary artery; LCx, left circumflex coronary artery; LMT, left main coronary artery; RCA, right coronary artery.
Clinical Outcomes
The median follow-up period after the index PCI was 2,101 days (interquartile range: 1,248–2,824 days). During the maximum 8-year follow-ups, the cumulative incidences of cardiac or non-cardiac deaths and myocardial infarctions were similar between the non-AD and AD groups, whereas the incidence of TLR was significantly higher in the AD group than in the non-AD group (12.9% vs. 4.4%, P=0.0002) ( Table 3 ) . Higher serum TGs and lower serum HDL-C levels persisted at the time of TLR, although LDL-C levels and the statin prescription rate were comparable between non-AD and AD lesions ( Table 4 ) . Kaplan–Meier curve analysis revealed that the cumulative incidence of clinically driven TLR was significantly higher in lesions with AD than in those without AD (hazard ratio [HR] 2.31, 95% confidence interval [CI] 1.57–5.37, P=0.0006) ( Fig.2 ) . After adjusting the confounding factors including age, sex, diabetes mellitus, AD, statin use, ISR lesions, total stent length, and minimum stent area using a Cox regression model, the risk of TLR was still significantly higher in AD lesions (adjusted HR 1.85, 95% CI 1.12–3.07, P=0.02). Isolated triglyceridemia or low HDL cholesterolemia did not affect the prevalence of TLR ( Supplemental Fig.1 ) .
Table 3. Cumulative event rates between with and without atherogenic dyslipidemia group.
| Non-AD (n = 1,883) | AD (n = 139) | P-value | |
|---|---|---|---|
| Death | 155 (8.2%) | 12 (8.6%) | 0.75 |
| Cardiac death | 28 (1.5%) | 2 (1.4%) | 0.82 |
| Non-cardiac death | 127 (6.7%) | 10 (7.2%) | 0.81 |
| MI | 7 (0.4%) | 0 (0%) | 0.42 |
| Clinically driven TVR | 244 (12.9%) | 27 (19.4%) | 0.12 |
| TLR | 84 (4.4%) | 18 (12.9%) | 0.0002 |
| Non TLR | 160 (8.5%) | 9 (6.5%) | 0.34 |
Data are presented as number (%) of patient events. P-values were calculated using the log-rank test. AD, atherogenic dyslipidemia; MI, myocardial infarction; TLR, target lesion revascularization; TVR, target vessel revascularization.
Table 4. Follow-up lipid data and the prevalence of statin administration at TLR.
| Non-AD (n = 103) | AD (n = 20) | P-value | |
|---|---|---|---|
| TC, mg/dL | 170±31 | 177±27 | 0.33 |
| LDL-C, mg/dL | 93±24 | 99±28 | 0.37 |
| HDL-C, mg/dL | 50±12 | 41±7 | 0.002 |
| TG, mg/dL | 118 [91-187] | 213 [126-271] | 0.01 |
| Statin use (%) | 63 (61) | 10 (50) | 0.36 |
Data are presented as the mean±SD, median [interquartile range], or number (%). AD, atherogenic dyslipidemia; HDL-C, high-density lipoprotein cholesterol; IHD, ischemic heart disease; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; TLR, target lesion revascularization.
Fig.2. Cumulative incidence of clinically driven TLR for the Non-AD and AD groups.
AD, atherogenic dyslipidemia; PCI, percutaneous coronary intervention; TLR, target lesion revascularization.
Supplemental Fig.1. Cumulative incidence of clinically driven TLR in (A) the entire population and (B) small stent use stratum according to TG and HDL-C levels.
HDL-C, high-density lipoprotein cholesterol; PCI, percutaneous coronary intervention; TG, triglyceride; TLR, target lesion revascularization.
Subgroup Analysis
Using subgroup analysis, we sought to explore the clinical, lesion, and procedural characteristics that had adverse effects on TLR in AD patients. Fig.3 displays the subgroup analysis for TLR based on the Cox proportional hazards analysis, with AD as a covariate. The relationships between clinical, lesion, and procedural characteristics and clinically driven TLR were evaluated for AD and non-AD lesions; significant interactions were observed between stent size and the effect of AD on clinically driven TLR (P for interaction =0.02), with a greater TLR risk, increased by AD in lesions treated with small stents (≤ 2.75 mm). Kaplan–Meier curve analysis for TLR revealed that small stent use for AD lesions had significantly worse outcomes than for non-AD lesions (HR 4.43, 95% CI 2.34–8.41, P＜0.0001), whereas no significantly elevated risk was found in non-small stent use for AD lesions compared with that for non-AD lesions (HR 1.35, 95% CI 0.65–2.83, P=0.44) ( Fig.4 ) . As observed in the overall study population, there was no significant elevated risk of TLR due to isolated triglyceridemia or low HDL cholesterolemia in the small stent use stratum ( Supplemental Fig.1 ) .
Fig. 3. Subgroup analysis of the influence of AD on clinically driven TLR by patient, lesion, and procedural characteristics and medication at PCI.
ACS, acute coronary syndrome; AHA, American Heart Association; BMI, body mass index; HR, hazard ratio; ISR, is-stent restenosis; MSA, minimum stent area; PCI, percutaneous coronary intervention; TLR, target lesion revascularization; y/o, years old.
Fig.4. Cumulative incidence of clinically driven TLR for Non-AD versus AD group in (A) no-small stent use and (B) small stent use stratum.
AD, atherogenic dyslipidemia; PCI, percutaneous coronary intervention; TLR, target lesion revascularization.
Risk Factors for TLR in Small Stent Use Stratum
The results of univariable and multivariable analyses of clinically driven TLR in the small stent use stratum are shown in Table 5 . In the small stent use stratum, after adjusting for confounders, the significant risk factors for TLR were AD (adjusted HR 3.00, 95% CI 1.53–5.93, P=0.004), statin use (adjusted HR 0.31, 95% CI 0.18–0.55, P＜0.0001), ISR lesions (adjusted HR 3.51, 95% CI 1.77–6.97, P=0.001), and total stent length (adjusted HR 1.02, 95% CI 1.01–1.03, P=0.0004). Furthermore, the sensitivity analysis adjusted for diabetes mellitus yielded similar findings.
Table 5. Univariable and multivariable analysis of risk factors for clinically driven TLR in small stent use stratum (1,183 lesions).
| Model 1 | Model 2 | |||||
|---|---|---|---|---|---|---|
| Variables | Unadjusted HR (95% CI) | P-value | Adjusted HR (95% CI) | P-value | Adjusted HR (95% CI) | P-value |
| Age | 0.99 (0.96-1.01) | 0.31 | 0.98 (0.95-1.01) | 0.11 | 0.98 (0.95-1.01) | 0.14 |
| Age > 75 years old | 0.81 (0.47-1.42) | 0.46 | ||||
| Male | 1.18 (0.65-2.14) | 0.57 | 0.85 (0.45-1.61) | 0.63 | 0.86 (0.46-1.63) | 0.65 |
| BMI | 0.99 (0.91-1.06) | 0.72 | ||||
| BMI ≥ 25 kg/m2 | 1.31 (0.73-2.35) | 0.37 | ||||
| Diabetes mellitus | 1.69 (0.99-2.86) | 0.053 | 1.38 (0.79-2.39) | 0.25 | ||
| Hypertension | 0.85 (0.46-1.56) | 0.6 | ||||
| Chronic kidney disease | 0.95 (0.56-1.63) | 0.87 | ||||
| Smoking | 1.17 (0.65-2.09) | 0.6 | ||||
| Previous MI | 0.62 (0.28-1.36) | 0.2 | ||||
| Previous PCI | 0.80 (0.47-1.36) | 0.41 | ||||
| Atherogenic dyslipidemia | 4.43 (2.34-8.41) | ＜0.0001 | 3.00 (1.53-5.93) | 0.004 | 2.90 (1.46-5.75) | 0.002 |
| Statin use | 0.37 (0.22-0.63) | 0.0002 | 0.31 (0.18-0.55) | ＜0.0001 | 0.31 (0.18-0.54) | ＜0.0001 |
| ACS presentation | 1.09 (0.51-2.30) | 0.83 | ||||
| B2/C lesion | 1.63 (0.74-3.60) | 0.2 | ||||
| CTO lesion | 0.88 (0.21-3.61) | 0.86 | ||||
| ISR lesion | 3.42 (1.76-6.63) | 0.001 | 3.51 (1.77-6.97) | 0.001 | 3.26 (1.62-6.57) | 0.001 |
| True bifurcation lesion | 1.41 (0.83-2.41) | 0.21 | ||||
| Calcified lesion | 1.08 (0.63-1.85) | 0.78 | ||||
| Aorto-ostial lesion | 0.80 (0.11-5.78) | 0.82 | ||||
| Total stent length | 1.02 (1.01-1.03) | 0.0003 | 1.02 (1.01-1.03) | 0.0004 | 1.02 (1.01-1.03) | 0.0001 |
| Long stenting (＞28 mm) | 1.66 (0.96-2.85) | 0.07 | ||||
ACS, acute coronary syndrome; BMI, body mass index; CTO, chronic total occlusion; ISR, is-stent restenosis; MI, myocardial infarction; PCI, percutaneous coronary intervention; TLR, target lesion revascularization
Discussion
The main findings of this study are summarized as follows: 1) AD was associated with significantly increased incidences of clinically driven TLR after EES implantation; 2) there was a significant interaction between stent size and AD status in the incidence of TLR; 3) unlike non-AD, the AD status at PCI was an independent predictor of TLR in lesions that were treated with a small stent (≤ 2.75 mm).
AD, characterized by reduced serum HDL-C and elevated serum TG, is considered a relevant risk factor for cardiovascular disorders 6 - 8) . It is a diagnostic criterion for metabolic syndrome associated with a high prevalence of coronary heart disease 6 , 7 , 13) . Despite using slightly different cutoff values of serum TG and HDL-C for the diagnosis of AD, the prevalence of AD in the current study was 6.9% consistent with previous reports (6%–17%) 6 , 8 , 13 - 16) . For example, in the ACCORD Lipid Study, fasting TG ≥ 204 mg/dL and HDL-C ≤ 34 mg/dL were defined as AD according to the tertile analysis of the study population 14) . In another study, AD was defined as ＞150 mg/dL fasting TG level and ＜40 mg/dL HDL-C level 8) . Although a TG level threshold of ＜150 mg/dL in the fasting state is currently used, the measurements are performed in the non-fasting state in most cases. The European Atherosclerosis Society and the task force of the ACC/AHA suggest a threshold value of 175 mg/dL for hypertriglyceridemia in the non-fasting state 17 , 18) . Recently updated Japanese guidelines also recommend 175 mg/dL as the cutoff value for non-fasting TG. Previous studies imply the possibility of a better predictive value of non-fasting TG than fasting TG for cardiovascular risk 19 , 20) . Thus, in the present study, we defined AD as a combination of non-fasting TG ≥ 175 mg/dL and HDL-C ＜40 mg/dL, and AD was associated with a higher rate of clinically driven TLR after EES implantation.
To the best of our knowledge, this is the first study exploring the association between AD and TLR in second-generation DES. An elevated TG/HDL-C ratio is a simple marker of AD and is associated with coronary atherosclerotic disease outcomes 21) . In the present study, TG/HDL-C ratio was considerably higher in the AD group than in the non-AD group (8.5±3.8 and 2.8±1.7, respectively). Kundi et al. and Matsumoto et al. demonstrated that AD, characterized by a high TG/HDL-C ratio, is associated with the presence of ISR 9 , 22) ; in these studies, the prevalence of ISR was 26.5% in the median of 161 days 9) and 13.8% in the median of 47 months 22) , respectively. These rates were higher than the prevalence of TLR in our study (4.1% in a median of 2,101 days). One of the reasons for this may be the lower rate of DES used in the above studies, which were 34.3% 9) and 69.5% 22) , respectively, including first-generation DES. TLR is not equivalent to restenosis. Since ISR is defined as ≥ 50% luminal narrowing regardless of symptoms or myocardial ischemia, the prevalence of ISR is generally higher than that of clinically driven TLR. Furthermore, TLR is associated not only with impaired quality of life and increased economic cost 23) but also with worse long-term mortality 24) . We considered TLR to be a more objective and relevant issue after EES implantation than restenosis and set TLR as the primary endpoint in this study. However, there were no differences in the prevalence of cardiac and non-cardiac deaths between non-AD and AD patients. In the current study, younger age and higher BMI of patients with AD may mask the adverse effect of AD on mortality due to the obesity paradox 25) .
Whether hypertriglyceridemia or low HDL cholesterolemia alone is an independent predictor of TLR or not remains controversial. Isolated triglyceridemia and low HDL cholesterolemia did not affect the prevalence of TLR in the present study; however, these lipid disorders may synergistically increase atherosclerotic risk 8) , which is still relevant after adjusting for LDL-C 26) . Patients with AD have elevated levels of small dense LDL particles, TG-rich very low-density lipoprotein, apolipoprotein B (Apo B), and oxidized LDL 8 , 27) , which, despite being pathogenic and related to stent restenosis, are not routinely measured in clinical practice 28 - 30) . We speculated that these atherogenic lipid phenotypes directly induced stent restenosis and contributed to TLR. AD status could be a surrogate marker of plasma atherogenicity for predicting high-risk patients.
We also hypothesized that AD is more strongly associated with TLR after EES implantation in a specific subgroup. We then explored the interaction between previously reported risk factors and AD for risk stratification of TLR. In the subgroup analysis based on the clinical, lesion, or procedural characteristics, the unfavorable effect of AD on TLR was prominent in cases of small EES use. The definition of a “small” vessel or stent varies in the medical literature. We defined small stents as stents with ≤ 2.75 mm diameter, consistent with other studies on EES 31 , 32) . Furthermore, in a large pooled analysis, Lee et al. demonstrated that 2.72 mm 33) diameter was the cutoff for EES failure, and the median stent diameter used in our study was 3.0 mm. Therefore, we considered that it was reasonable to use a cutoff stent diameter of 2.75 mm. Furthermore, after the inclusion of other atherogenic variables in the Cox model, AD remained an independent predictor of TLR, post-implantation of a small EES. Small DES is significantly more effective than BMS in reducing TVR at long-term follow-up and is frequently implanted nowadays 34) . In the present study, small EES were used in 39.3% (1,181 lesions) of the analyzed PCI lesions (3,014 lesions), and extensive monitoring was needed for patients with AD who underwent PCI with smaller stents. Previous imaging-based studies have demonstrated that neointimal hyperplasia (NIH) emerged as the main cause of ISR in the early (＜1 year) phase, whereas neoatherosclerosis (NA) was dominant in the late (＞1 year) phase and increased over time after second-generation DES implantation 35 , 36) . In the current study, the difference in the Kaplan–Meier curve of TLR between AD and non-AD patients was observed in the early period (＜1 year), and the curve separated gradually in the late period (＞1 year), indicating that both NIH and NA were involved in the mechanisms of TLR in patients with AD. However, we did not confirm whether the TLR mechanism in our study was NIH or NA because almost all TLR lesions were assessed using IVUS and not optical coherence tomography at re-revascularization, therefore, further investigation is necessary. We also analyzed IVUS findings at the time of TLR ( Supplemental Table 1 ) . Stent expansion assessed by the conventional expansion index or minimum stent area/vessel ratio 37) was adequately achieved in TLR lesions with AD. Compared with the no-small stent use stratum, less neointimal tissue resulted in worse lumen outcomes in the small stent use stratum. Thus, the deteriorative effect of AD on TLR may be more prominent in smaller stents.
Supplemental Table 1. Comparison of pre-PCI intravascular ultrasound findings at TLR between non-AD lesions and AD lesions.
| Non-AD (n = 103) | AD (n = 20) | P-value | |
|---|---|---|---|
| No-small stent use | 60 | 8 | |
| IVUS | 52 | 8 | |
| Pre-dilatation before IVUS | 23 | 3 | 0.72 |
| Plaque area, % | 77±18 | 82±5 | 0.47 |
| MSA, mm2 | 8.2±2.4 | 8.0±3.3 | 0.84 |
| MLA, mm2 | 2.9±1.3 | 2.5±1.0 | 0.37 |
| Neointimal tissue area, mm2 | 5.2±0.4 | 5.5±0.7 | 0.80 |
| Neointimal tissue/stent area, % | 63±13 | 68±9 | 0.30 |
| Stent expansion, % | 109±23 | 107±22 | 0.83 |
| MSA/Vessel, % | 52±12 | 49±17 | 0.54 |
| Small stent use | 43 | 12 | |
| IVUS | 37 | 11 | |
| Pre-dilatation before IVUS | 11 | 3 | 0.68 |
| Plaque area, % | 79±7 | 74±7 | 0.19 |
| MSA, mm2 | 5.3±1.9 | 5.2±0.5 | 0.95 |
| MLA, mm2 | 2.3±0.8 | 2.4±0.8 | 0.62 |
| Neointimal tissue area, mm2 | 3.0±1.5 | 2.8±0.7 | 0.80 |
| Neointimal tissue/stent area, % | 56±14 | 55±15 | 0.92 |
| Stent expansion, % | 100±22 | 103±25 | 0.23 |
| MSA/Vessel, % | 47±11 | 59±3 | 0.03 |
Data are presented as the mean±SD, or number. AD, atherogenic dyslipidemia; IVUS, intravascular ultrasound; MLA, minimum lumen area; MSA, minimum stent area; PCI, percutaneous coronary intervention; TLR, target lesion revascularization.
According to previous reports, several medical interventions, such as statins 5) or beta-blockers 38) , can potentially prevent TLR after EES implantation. Notably, AD has been implicated as an independent risk factor after PCI, even in patients treated with statins 22) . Several large-scale studies, including ACCORD LIPID, have shown that a specific subgroup with high TG and low HDL-C levels might benefit from treating dyslipidemia 39 , 40) . There is no evidence to support the direct protective role of HDL-C against cardiovascular events. Cholesteryl ester transfers the protein inhibitors to increase HDL-C levels but could not show any benefit in reducing cardiovascular mortality on statin therapy 41 , 42) , suggesting that the quality of HDL particles is more important than their quantity. Fibrates and peroxisome proliferator-activated receptor alpha (PPARα) agonists are the most widely used drugs to lower TG levels and modestly increase HDL-C levels; however, several randomized fibrate trials for AD treatment have found conflicting results 43) . A novel selective PPARα modulator, pemafibrate, with stronger selectivity for PPARα and a favorable safety profile for combination with statins, is currently available. Based on a recent study, pemafibrate decreases the atherogenic lipoprotein marker Apo B/Apo A-I ratio 44 , 45) and suppresses stent restenosis in a pig model 46) . Even though the prescription rate of TG-lowering drugs such as fibrates was not evaluated in the present study, our findings suggest that aggressive medical intervention might be considered to prevent TLR after PCI with smaller stents. In addition, patients with AD were more obese and had smoking behavior, as observed in the present study. Therefore, lifestyle improvements 47) , such as dietary restriction, smoking cessation, exercise, and weight loss, are also desirable options for treating AD.
Our study had several limitations. First, it was a retrospective, nonrandomized, observational study with unsuspected selection biases and confounding factors. Second, there was a substantial difference in the clinical background of AD and non-AD patients and lesions. Third, the relatively small number of patients with AD and the low prevalence of clinically driven TLR of EES might reduce the statistical power to assess the genuine interaction between AD and other risk factors. Fourth, a selection bias may have affected the results because a routine follow-up examination was not performed and the prevalence of coronary angiography, CT, or cardiac scintigraphy in patients with and without AD was not evaluated. Fifth, the prevalence of patients taking TG-lowering drugs such as fibrates was not evaluated, and how AD parameters fluctuated during the follow-up period was unclear. Sixth, a lower frequency of statin use in our population compared with a more modern cohort may have influenced the TLR rate.
Conclusion
AD during PCI was associated with a significantly higher risk of clinically driven TLR. Combining AD status with stent size information allowed for better risk stratification.
Acknowledgement
The authors appreciate the efforts of the members of the cardiac catheterization laboratory of the Koto Memorial Hospital.
Sources of Funding
This study did not receive any specific funding.
Conflicts of Interest
The authors have no conflicts of interest.
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