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High high-density lipoprotein-cholesterol reduces risk and extent of percutaneous coronary intervention-related myocardial infarction and improves long-term outcome in patients undergoing elective percutaneous coronary intervention

Katherine J.E. Sattler , Jörg Herrmann , Şehriban Yün , Nils Lehmann , Zhen Wang , Gerd Heusch , Stefan Sack , Raimund Erbel , Bodo Levkau
DOI: http://dx.doi.org/10.1093/eurheartj/ehp183 1894-1902 First published online: 27 May 2009

Abstract

Aims The study tested whether high-density lipoprotein-cholesterol (HDL-C) has an effect on percutaneous coronary intervention (PCI)-induced myocardial infarction and its prognosis. Elevation of cardiac troponin I (cTnI) > 3× upper normal limit after PCI is defined as PCI-related myocardial infarction (PMI) and is associated with a negative prognosis. No data exist on the relationship of HDL-C to PMI and PMI-related outcome.

Methods and results Pre-procedural HDL-C levels and post-procedural peak cTnI levels were collected in 350 patients undergoing PCI. Data were analysed for PMI and for acute myocardial infarction (AMI) during follow-up. Patients with PMI (n = 115) had lower HDL-C levels than patients without PMI [n = 235; 1.17 mmol/L (0.75–2.51) vs. 1.27 mmol/L (0.70–2.87), P < 0.001]. Pre-procedural HDL-C levels were inversely related to the occurrence of PMI [odds ratio for PMI: 0.884, 95% CI: 0.80, 0.98; P = 0.02 for an HDL-C-increment of 5 mg/dL (0.13 mmol/L)] and to AMI during follow-up [hazard ratio (HR): 0.697, 95% CI: 0.54, 0.90; P = 0.005]. The occurrence of PMI was associated with an elevated HR for AMI (4.702, 95% CI: 1.79, 12.37; P = 0.002). Low-risk levels of pre-procedural HDL-C [men ≥40 mg/dL (≥1.03 mmol/L), women ≥45 mg/dL (≥1.16 mmol/L)] did not influence the negative effects of PMI on outcome (HR: 5.510, 95% CI: 1.43, 21.31; P = 0.013) and reduction of AMI-free survival [mean AMI-free survival time with PMI: 1167.5 days (95% CI: 1098.27, 1236.67) vs. 1240.7 days (95% CI: 1220.94, 1290.49) without PMI; log-rank P = 0.005].

Conclusion Small increases in HDL-C in patients undergoing elective PCI convert into a substantial reduction of risk for PMI, which has adverse effects on the long-term prognosis. Patients with PMI are at a high risk for AMI at any HDL-C level and therefore should receive particular monitoring by the treating physician over a long period after PCI.

  • High-density lipoprotein-cholesterol
  • Coronary artery disease
  • PCI-related myocardial infarction
  • Prognosis

Introduction

Percutaneous coronary intervention (PCI) is the major strategy to treat coronary artery stenosis.1 However, elevations of cardiac biomarkers such as cardiac troponin T or I (cTnT or cTnI) or creatine kinase (CK) are observed in 30–70% of patients after PCI2 and are related to procedural characteristics and complications.25 Magnetic resonance imaging has established the pathophysiological substrate of these biomarker elevations after PCI to be a peri-procedural myocardial infarction.6 Accordingly, the Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction has suggested that the elevation of biomarkers more than three times the 99th percentile upper reference limit after PCI should be defined as infarction type 4a or PCI-related myocardial infarction (PMI).7 By comparative analysis, the clinical significance of PMI and spontaneous acute myocardial infarction (AMI) in regard to prognosis is similar,8 and consequently, PMI is associated with a higher incidence of long-term mortality and adverse cardiac events.9,10

High-density lipoproteins are a potent atheroprotective factor as shown in numerous epidemiological and interventional studies. Therapeutic administration of reconstituted high-density lipoprotein (rHDL) both in animal models and patients with coronary artery disease (CAD) has been shown to promote lesion stabilization.11,12 In addition, we have shown that administration of native HDL in mice prior to experimental myocardial ischaemia protected against reperfusion injury in a lesion-independent manner.13 However, no data exist on the relationship between HDL-cholesterol (HDL-C) and PMI or PMI-related outcome. Thus, we tested the hypothesis that high endogenous HDL-C levels may have a beneficial effect on the incidence and extent of PMI, and assessed the association of HDL-C levels and PMI on the long-term outcome in patients undergoing elective PCI.

Methods

Patient population

Seven hundred and thirty-one patients undergoing elective PCI between 2004 and 2006 without acute coronary syndrome (ACS) defined as ST-elevation infarction or non-ST-elevation AMI within 4 weeks prior to intervention were retrospectively included at the West German Heart Center, University Hospital Essen, Essen, Germany. Of these, 350 patients were included who had a complete lipid profile and consecutive cTnI and CK measurements. Patients were not eligible if one of the following criteria was present: (i) elevated levels of cTnI prior to intervention (n = 146), (ii) missing lipid (n = 58) or cTnI values after PCI (n = 44), and (iii) chronic renal insufficiency with a reduced glomerular filtration rate ≤60 mL/min (n = 175; in several patients, more than one exclusion criterion was found). Glomerular filtration rate was calculated from serum creatinine levels according to the Wright-formula, which takes into account age, gender, and body surface area.14

Percutaneous coronary artery intervention

The indication for coronary angiography was based on the ACC/AHA recommendations and was performed according to standard protocols by experienced invasive cardiologists. Interventional procedures included percutaneous transluminal coronary angioplasty (PTCA), stent-implantation, rotablation, and combined PTCA/brachytherapy. If necessary, more than one lesion was treated during the procedure. Vessel closure was performed with routinely used vascular closure systems. A weight-adjusted bolus of heparin and an intracoronary bolus of 0.2 mg nitroglycerin were routinely given after the intubation of each coronary artery and prior to angiography. Clopidogrel (75 mg/day after a loading dose of 300 or 600 mg depending on the time of initiation of clopidogrel prior to intervention) was started in addition to aspirin (100 mg/day). Intra-procedural complications, defined as vessel wall dissection, side branch occlusion, occlusion of vessels distal to the target lesion, plaque shift, or no-reflow were recorded as documented in the catheterization report during the intervention by the operating physician. Intra-procedural complications were counted on a per-patient base and not as separate events. Administration of a glycoprotein IIb/IIIa receptor inhibitor and post-procedural use of intravenous heparin were left to the operating physician's discretion.

Lipid profile and plasma markers

Cardiac troponin I and CK activity was determined in venous blood samples on the day prior to PCI, 6 h after PCI and again 12–24 h after PCI, and in the case of the occurrence of symptoms which were interpreted as a post-procedural ischaemic event. The peak value of cTnI was used for statistical analysis. For measurement of cTnI, a colorimetric immunoassay (Dimension cTnI, Dade Behring, Newark, DE, USA) was used. This test has a sensitivity of 0.04 ng/mL with an upper normal value (UNL) of 0.1 ng/mL according to the manufacturer's information. In accordance with the consensus document of the Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction,7 cTnI elevation of >3× UNL was classified as PMI if it had occurred within 24 h after PCI. Creatine kinase activity was measured with an enzymatic assay based on the modified Szasz-procedure using the activator n-acetylcystein [creatine kinase (CK-NAC), Semen Healthcare Diagnostics, Eschborn, Germany]. This assay has an UNL for men of 174 U/L and for women of 140 U/L. Total cholesterol, low-density lipoprotein-cholesterol (LDL-C), HDL-C, triglycerides, serum creatinine, HbA1c, and C-reactive protein were routinely measured in a fasting state in venous plasma using standard assays. Data were considered appropriate for analysis if the parameters were measured during the hospital stay for PCI, or within 14 days prior to intervention when patients presented to the hospital on an outpatient basis for evaluation of the PCI-procedure. In case patients presented earlier than 14 days prior to the procedure or if parameters were determined on a subsequent presentation, the data were considered invalid and these patients were not included. All blood values were measured in the central laboratory of the University Hospital Essen.

Follow-up

Follow-up data were collected during January and February 2008. Data were obtained by telephone interviews with the patients or their relatives and by inviting patients to complete a standardized questionnaire which was sent to the patients during the follow-up collection period. Endpoint of follow-up was defined as the occurrence of spontaneous AMI (ST-elevation infarction or non-ST-elevation myocardial infarction occurring >24 h after PCI), if the AMI had occurred during the initial stay (hospital records) or thereafter (according to the general physician's or to hospital records).

Statistical analysis

Data are expressed as mean ± SD or median (range) for continuous variables, and frequency count and percentage for qualitative variables. Comparison of groups was performed with Mann–Whitney rank-sum test for quantitative variables and by χ2-test for percentages of qualitative variables. In case of multiple comparisons, a Tamhane-T2 test for post hoc analysis was performed with indication of the P-value and the confidence interval. Spearman's rank-order correlation was used to assess the association between HDL-C levels and levels of cTnI. Univariate logistic regression analyses were performed with the dependent variable ‘PMI absent: 0, PMI present: 1’ and the independent factor ‘HDL-C level’ as well as with the independent factor, ‘LDL-C level’ and with the parameter ‘treatment modalities (combination of balloon dilation/stent implantation or stent implantation only)’. Logistic regression analysis was additionally performed with the dependent variable ‘intra-procedural complication absent: 0, present: 1’ and the independent factor ‘treatment modalities (combination of balloon dilation/stent implantation or stent implantation only)'. A multivariable logistic regression analysis utilizing single-step block entry of the predictor variables was performed with the dependent variable ‘PMI absent: 0, PMI present: 1’ and the predictor variables ‘HDL-C levels, age, and gender’, and with the predictor variables ‘HDL-C levels, age, gender, triglycerides, LDL-C, impaired glucose tolerance, and intake of statins’. Results are described as odds ratios (ORs) with 95% confidence intervals (95% CIs). Cox regression analyses using single-step block entry of independent factors were used to determine the relationship between AMI-free survival time after PCI and the independent factors ‘HDL-C level’ and ‘PMI’, and with the independent factor ‘low-risk HDL-C level’. The definition of ‘low-risk HDL-C levels’ was based on the definition of the European guidelines on cardiovascular disease prevention,15 which define low-risk HDL-C levels as levels in men ≥40 mg/dL and in women ≥45 mg/dL. Results are described as hazard ratios (HRs) with 95% CIs. Analysis of AMI-free survival time after PCI was performed according to the Kaplan–Meier procedure, evaluating group differences by log-rank test. One patient reported diagnosis of silent AMI during follow-up assessment. This patient was not included into the Kaplan–Meier analysis for uncertainty of the event date. For 2 × 2-crosstabulation, the exact two-sided significance values are given. P-values are understood to be strictly descriptive. Statistical significance was assumed for P < 0.05. All analyses and graphs were performed with SPSS 17.0 (Chicago, IL, USA), except the Forest-plot, which was drawn by an online available graph plotting program.16

Results

High pre-procedural high-density lipoprotein-cholesterol levels reduce the risk for percutaneous coronary intervention-related myocardial infarction

Percutaneous coronary intervention-related myocardial infarction developed in 115 of 350 patients within 24 h after intervention (32.9%; cTnI: median 0.96 ng/mL, range 0.31–47.37 ng/mL). Patients with PMI had lower HDL-C-values than those without PMI [1.17 mmol/L (0.75–2.51) vs. 1.27 mmol/L (0.70–2.87), P = 0.001, Figure 1A]. There were no differences between the two groups in regard to other lipid parameters or to demographic characteristics (Tables 13).

Figure 1

Relationship between pre-procedural high-density lipoprotein-choleterol levels and percutaneous coronary intervention-related infarction. (A) Patients without percutaneous coronary intervention-related infarction had higher pre-procedural high-density lipoprotein-cholesterol-values than those with percutaneous coronary intervention-related myocardial infarction [1.27 mmol/L (0.70–2.87) vs. 1.17 mmol/L (0.75–2.51), P < 0.001, 95% CI: 0.001, 0.002]. Circles indicate outliers and asterisks indicate extreme values. (B) Relationship of pre-procedural high-density lipoprotein-cholesterol levels at 5 mg/dL (0.13 mmol/L) increment with the odds for percutaneous coronary intervention-related myocardial infarction. The numbers in parentheses show the odds ratios and the 95% confidence intervals. HDL-C, high-density lipoprotein-cholesterol; PCI, percutaneous coronary intervention; PMI, PCI-related myocardial infarction.

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Table 1

Baseline characteristics of the patient populationa

CharacteristicsTotal population (n = 350)No PMI (n = 235)PMI (n = 115)P-value (confidence interval)
Male, no. (%)287 (82)189 (80.4)98 (85.2)0.30
Age (years)65.0 (31.0–84.0)65.0 (36.0–84.0)65.0 (31.0–80.0)0.87 (0.86, 0.87)
BMI (kg/m2)27.0 (18.1–41.3)26.9 (18.1–39.0)27.6 (20.3–41.3)0.18 (0.17, 0.18)
Peak cTnI after intervention (ng/mL)0.13 (0–47.37)0.06 (0.00–0.30)0.96 (0.31–47.37)<0.001 (0.00, 0.00)
Peak CK after intervention (U/L)102.5 (20.0–1617.0)86.0 (20.0–509.0)128.0 (40.0–1617.0)<0.001
Number of patients with peak CK > 3× UNL, no. (%)10.0 (2.9)0 (0.0)10.0 (8.7)<0.001
Total cholesterol (mmol/L)4.61 (2.36–8.88)4.64 (2.77–8.88)4.56 (2.36–8.78)0.33 (0.32, 0.34)
HDL-cholesterol (mmol/L)1.24 (0.70–2.87)1.27 (0.70–2.87)1.17 (0.75–2.51)0.001 (0.001, 0.002)
LDL-cholesterol (mmol/L)2.49 (0.57–5.59)2.51 (0.57–5.59)2.38 (0.75–5.23)0.29 (0.28, 0.30)
Triglycerides (mmol/L)1.56 (0.33–14.24)1.50 (0.50–9.62)1.62 (0.33–14.24)0.15 (0.14, 0.16)
C-reactive protein (mg/dL)0.1 (0.0–7.7)0.1 (0.0–7.7)0.1 (0.0–2.6)0.44 (0.43, 0.45)
Current smoker, no. (%)39 (11.9)22 (10.0)17 (15.7)0.15
Hypertension, no. (%)344 (99.4)229 (99.1)115 (100.0)0.56
Hypercholesterolaemia, no. (%)327 (95.1)217 (94.3)110 (96.5)0.44
Impaired glucose metabolism, no. (%)b123 (37.5)75 (34.4)48 (43.6)0.12
  • BMI, body mass index; CK, creatine kinase; cTnI, cardiac troponin I; HDL-cholesterol, high-density lipoprotein-cholesterol; LDL-cholesterol, low-density lipoprotein-cholesterol; UNL, upper normal limit.

  • aValues given are median and range for continuous and number and percentage for qualitative data.

  • b‘Impaired glucose metabolism’ combines patients with diagnosed diabetes mellitus and patients with HbA1c levels >6.05% regardless of known diagnosis of diabetes mellitus.

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Table 2

Symptoms and history of coronary artery disease at time of enrolment and characteristics of the percutaneous coronary intervention-procedurea

CharacteristicsNo PMI (n = 235)PMI (n = 115)P-value
Extent of disease, no. (%)
 1-vessel-disease47 (20.0)17 (14.9)
 2-vessel-disease65 (27.7)32 (27.8)
 3-vessel-disease123 (52.3)66 (57.4)0.46
Ejection fraction (%)b64.1 ± 11.364.55 ± 11.40.81
Previous PCI, no. (%)178 (76.7)86 (75.4)0.79
Previous myocardial infarction, no. (%)79 (33.8)37 (32.5)0.90
Type of intervention, no. (%)c,d
 Multilesion-intervention33 (14.0)18 (15.7)
 Multivessel-intervention18 (7.7)15 (13.0)0.23
 Balloon angioplasty only8 (3.4)2 (1.7)0.51
 Stent implantation without pre-dilation148 (63.0)51 (44.3)0.001
 Balloon dilation and stent implantation77 (32.8)62 (53.9)<0.001
 Balloon dilation and brachytherapy5 (2.1)1 (0.9)0.67
 Rotablation1 (0.4)2 (1.7)0.26
Number of stents implanted1.43 ± 0.841.75 ± 0.970.002
Intra-procedural complications, no. (%)e21 (8.9)20 (17.4)0.03
  • PCI, percutaneous coronary intervention.

  • aValues given are median and range for continuous and number and percentage for qualitative data except the ejection fraction and the number of stents which are presented as mean ± standard deviation.

  • bThe ejection fraction was obtained by levocardiography and was available in 196 (56%) patients [137 patients (58.3%) without PMI and 56 patients (48.7%) with PMI].

  • c‘Multilesion intervention’ was defined as the treatment of several target lesions in one single vessel and ‘multivessel intervention’ was defined as the treatment of at least one lesion in more than one target vessel; thus, these types of intervention are mutually exclusive. The complimentary treatment type of both would be the treatment of a single target lesion in a single vessel.

  • dSeveral patients were treated with more than one type of intervention (except when treated with balloon angioplasty only), thus the number of observations exceeds the number of patients per group.

  • eThe term ‘intra-procedural complications’ comprises the occurrence of dissection, side branch or distal vessel occlusion, plaque shift and no-reflow during the intervention (see the Methods section for detailed information). Five patients in the non-PMI group were not assessed for complications.

View this table:
Table 3

Medication of the patient population at time of enrolmenta,b

CharacteristicsNo PMI (n = 235)PMI (n = 115)P-value
Aspirin, no. (%)188/207 (93.5)94/107 (93.1)1.00
Beta-blockers, no. (%)187/201 (93.0)92/101 (91.1)0.65
ACE-inhibitors, no. (%)148/201 (73.6)69/101 (68.3)0.35
AT1-blockers, no. (%)32/201 (15.9)19/101 (18.8)0.52
Diuretics, no. (%)116/201 (57.7)54/101 (53.5)0.54
Calcium channel-blockers, no. (%)34/201 (16.9)17/101 (16.8)1.00
Clopidogrel at time of enrolment, no. (%)113/201 (56.2)48/101 (47.5)0.18
Digitalis, no. (%)6/201 (3.0)5/101 (5.0)0.52
CSE-inhibitors, no. (%)176 (74.9)90 (78.3)0.85
Clopidogrel 600 mg loading dose, no. (%)61 (26.0)41 (35.7)0.23 (0.22, 0.24)
Glycoprotein IIb/IIIa-inhibitors, no. (%)4 (1.7)9 (7.8)0.007
  • ACE-inhibitors, angiotensin-converting enzyme-inhibitors; AT1-blockers, angiotensin receptor type I-blockers; CSE-inhibitors, cholesterol synthase enzyme-blockers.

  • aValues given are median and range for continuous and number and percentage for qualitative data.

  • bFor several patients, specification of drug intake at time of enrolment was not available. Thus, data are given as the number of positive observations/total recorded counts of observations (per cent of total recorded counts of observation).

Pre-procedural HDL-C levels were weakly and inversely correlated to the peak cTnI levels after PCI (r = − 0.11, P = 0.042). The HDL-C levels prior to PCI were significantly related to the occurrence of PMI. For an increment of 5 mg/dL (0.13 mmol/L) of HDL-C, the OR was 0.884 (95% CI: 0.80, 0.98; P = 0.02), demonstrating a reduction of the risk for infarction after PCI procedure by 11.6% per 5 mg/dL increment of HDL-C prior to PCI. In contrast to these findings, the levels of LDL-C [per increment of 10 mg/dL (0.26 mmol/L)] were not related to PMI (OR: 0.97, 95% CI: 0.91, 1.04; P = 0.4). The probability to develop PMI was dependent on procedural characteristics as well: patients without PMI were more often treated with stent implantation without a pre-dilation, whereas those with PMI were more often treated with the combination of balloon dilation/stent implantation (Table 2). Accordingly, treatment with stent implantation lowered the probability to develop PMI (OR: 0.68, 95% CI: 0.54, 0.85; P < 0.001), whereas the combination of balloon dilation/stent implantation increased the probability for PMI (OR: 1.33, 95% CI: 1.15, 1.55; P < 0.001). In patients with PMI, intra-procedural complications (as defined in detail in the Methods section) were more often recorded than in patients without PMI (17.4 vs. 8.9%, P = 0.034). As expected, the occurrence of intra-procedural complications was dependent on the type of intervention, as interventions applying multiple manipulations of the target lesion (combination of balloon dilation/stent implantation) were predictive for intra-procedural complications (OR: 1.57, 95% CI: 1.24, 1.98; P < 0.001), contrary to procedures treating the target lesions with sole stent implantation without any additional dilation (OR: 0.51, 95% CI: 0.36, 0.73; P < 0.001). At the time of intervention, 76% of all patients were on statin medication (Table 3). Total cholesterol levels were lower in treated patients when compared with untreated patients [4.61 mmol/L (2.36–8.88) vs. 5.13 mmol/L (2.85–7.61), P = 0.04], whereas HDL-C, LDL-C, and the LDL-C:HDL-C ratio did not differ. Intake of statins was neither associated with lower post-interventional levels of cTnI [0.13 ng/mL (0.00–41.53) vs. 0.12 ng/mL (0.00–2.67), P = 0.77] nor with lower incidence of PMI (P = 0.85).

In the multivariable logistic regression analysis including the independent predictors ‘HDL-C level’, ‘age’, and ‘gender’, the association between the pre-procedural HDL-C levels and the occurrence of PMI remained significant [5 mg/dL (0.13 mmol/L) increment of HDL-C: OR: 0.88, 95% CI: 0.79, 0.98; P = 0.02], whereas an association was neither observed between age (per increase of 5 years) nor gender and PMI (age: OR: 1.04, 95% CI: 0.91, 1.19; P = 0.60; gender: OR: 0.87, 95% CI: 0.46, 1.63; P = 0.66). When further factors were added as independent predictors (see the Methods section), the effect of HDL-C on PMI persisted [5 mg/dL (0.13 mmol/L) increment of HDL-C: OR: 0.91, 95% CI: 0.80, 1.02; P = 0.1], whereas the other parameters were not associated with PMI (Figure 1B).

High-density lipoprotein-cholesterol levels determine outcome after percutaneous coronary intervention

Follow-up was available for 88.6% of all patients (87.0% of the patients with previous PCI-related myocardial infarction vs. 89.4% of the patients without previous PCI-related myocardial infarction, P = 0.59). Median follow-up time was 873 days (inter-quartile range 684.0–1043.0 days). During follow-up, spontaneous AMI occurred in 19 patients (6.1%) after 160 days (inter-quartile range 59.0–550.0 days). The cumulative incidence of AMI during follow-up was higher in patients with previous PMI than without PMI (13.0 vs. 2.9%, P = 0.001), and the incidence rate was higher in patients with previous PMI than without previous PMI (PMI: 0.44/100 patient-days vs. 0.29/100 patient-days). The association of PMI with an impaired outcome was expressed by a worse AMI-free survival time in patients with previous PMI [mean AMI-free survival time with PMI: 1128.1 days (95% CI: 1057.71, 1198.49) vs. 1230.0 days (95% CI: 1207.44, 1252.63) of mean AMI-free survival time without PMI; log-rank P = 0.001] and an HR of 4.702 (95% CI: 1.79, 12.37; P = 0.002).

Per 5 mg/dL (0.13 mmol/L) increment of pre-procedural HDL-C, the HR for AMI during follow-up was reduced by 30.3% (HR: 0.697, 95% CI: 0.54, 0.90; P = 0.005). Adding PMI to the analysis showed an elevated HR for AMI after the occurrence of PMI (HR: 3.923, 95% CI: 1.48, 10.40; P = 0.006), and the inverse association between incremental levels of HDL-C and AMI-free survival time remained (HR: 0.732, 95% CI: 0.566, 0.948; P = 0.018).

Percutaneous coronary intervention-related myocardial infarction-mediated risk for acute myocardial infarction persists despite ‘low-risk high-density lipoprotein-cholesterol’ levels

We next assessed whether the levels of HDL-C considered a marker of low cardiovascular risk [‘low-risk HDL-C’; HDL-C in men ≥40 mg/dL (1.03 mmol/L) and in women ≥45 mg/dL (1.16 mmol/L)] or of high cardiovascular risk [‘high-risk HDL-C’; HDL-C in men <40 mg/dL (1.03 mmol/L) and in women <45 mg/dL (1.16 mmol/L)15] were applicable to the present study population. Indeed, patients with ‘low-risk HDL-C’ had a better AMI-free survival than those with ‘high-risk HDL-C’ (HR: 0.240, 95% CI: 0.10, 0.60; P = 0.002) and a better AMI-free survival time [mean AMI-free survival time with ‘low-risk HDL-C’: 1222.8 days (95% CI: 1197.3, 1248.2) vs. 1042.4 days (95% CI: 952.6, 1132.3) in ‘high-risk HDL-C’, log-rank P = 0.001]. The numbers of patients with PMI and of those with intra-procedural complications were comparable between the patients with ‘low-risk HDL-C’ and those with ‘high-risk HDL-C’ (P > 0.05). ‘Low-risk HDL-C’ prior to PCI did not influence the effects of PMI on outcome as the occurrence of PMI after PCI was still associated with an elevated HR for AMI during follow-up (HR: 5.510, 95% CI: 1.43, 21.31; P = 0.013) and a reduced AMI-free survival time [mean AMI-free survival time with PMI: 1167.5 days (95% CI: 1098.27, 1236.67) vs. 1240.7 days (95% CI: 1220.94, 1290.49) of mean AMI-free survival time without PMI; log-rank P = 0.005]. In patients with ‘high-risk HDL-C’, the occurrence of PMI after PCI was also associated with an elevated HR for AMI (HR: 3.060, 95% CI: 0.76, 12.26; P = 0.11; Figure 2).

Figure 2

Relationship between pre-procedural high-density lipoprotein-cholesterol levels, percutaneous coronary intervention-related infarction and acute myocardial infarction. Hazard ratios with 95% confidence intervals for acute myocardial infarction according to ‘low-risk’ levels of high-density lipoprotein-choleterol [men ≥40 mg/dL (≥1.03 mmol/L) and women ≥45 mg/dL (≥1.16 mmol/L)] and ‘high-risk’ levels of high-density lipoprotein-cholesterol [men <40 mg/dL (<1.03 mmol/L) and women <45 mg/dL (<1.16 mmol/L)] in the whole study population and in patients with percutaneous coronary intervention-related myocardial infarction. AMI, acute myocardial infarction; HDL-C, high-density lipoprotein-cholesterol; PCI, percutaneous coronary intervention; PMI, PCI-related myocardial infarction.

Discussion

The major findings of this study are: (i) pre-procedural HDL-C levels reduce the risk for PMI after elective PCI, (ii) increasing HDL-C levels are associated with a diminished extent of PCI-associated myocardial necrosis, (iii) pre-procedural HDL-C levels determine the outcome after elective PCI in respect to the occurrence of AMI, and (vi) PMI is associated with a negative long-term prognosis in patients with HDL-C levels considered of both high and low risk (<40 mg/dL in men and <45 mg/dL in women, and ≥40 mg/dL in men and ≥45 mg/dL in women, respectively15).

Potential mechanisms of high-density lipoprotein-cholesterol-mediated protection against percutaneous coronary intervention-related myocardial infarction: beneficial effects on both plaque and myocardium

Myocardial necrosis during PCI depends on interventional characteristics (balloon inflation time, maximal inflation pressure, and number of stents) and procedural complications (side branch occlusions or distal vasoconstriction). These factors determine the extent and duration of ischaemia prior to reinstitution of blood flow,25 and thus the extent of the subsequent ‘ischaemia/reperfusion injury’. In addition, the characteristics of the targeted atherosclerotic lesion influence the risk of microembolization in the perfusion territory of the intervened artery: manipulation of lipid-rich lesions has been associated with surrogate markers of microembolization such as no-reflow, microvascular dysfunction, and cardiac marker elevation.1721 The actual existence of microemboli after PCI has been visualized via intracoronary Doppler ultrasound and their numbers have been correlated with cTnI elevation and reduction of coronary flow velocity reserve.22

The beneficial effect of HDL-C on PMI we have observed in our study may be due to its impact both on the myocardium and the plaque. High HDL-C levels may have had induced a more stable plaque morphology prior to the intervention, thus reducing the incidence of microembolization when the PCI was performed. During the procedure and in its aftermath, high HDL-C levels may have protected the myocardium against the procedure-related micro-infarctions via their potent anti-adhesive, anti-oxidative, and anti-inflammatory properties, and by preserving the microvascular integrity and/or by stimulation of cardiac perfusion.13,2328 In support of these notions, we have shown in previous studies that myocardial injury and post-ischaemic inflammation after transient coronary occlusion in mice were dramatically attenuated by administration of native human HDL,13 and that human HDL increased cardiac perfusion in mice. Furthermore, high HDL-C levels have been shown to stabilize plaques, attenuate lesion progression, and even promote lesion regression in experimental animal models29 and patients with CAD,30,31 and exogenous administration of rHDL has been shown to reduce plaque volume and promote lesion stabilization in animals11 and patients.12 Such HDL-C-induced changes seem to affect particularly the lipid core and inflammatory content of plaques.32,33 Thus, both myocardium- and plaque-specific biological properties of HDL may be responsible for its protective effect against PCI-related myocardial injury.

Pre-procedural high-density lipoprotein-cholesterol, percutaneous coronary intervention-related myocardial infarction, and consequences for prognosis

Our results are in line with other studies associating PCI-related myocardial injury with higher incidence of long-term mortality and adverse cardiac events.9,10 However, our results demonstrate that pre-procedural HDL-C levels determine the extent and severity of PMI after elective PCI, and thus clearly influence injury-dependent prognosis. The mechanism how high HDL-C prevents the adverse long-term outcome may be based on its aforementioned effects on cardiac perfusion, myocardial survival, and possibly remodelling.23 In support of our observations for patients with stable CAD, previous studies on patients with ACS also showed a significant inverse relationship between baseline HDL-C levels and outcome.34,35 In the MIRACL trial,34 a reduction of the risk for cardiovascular events of 1.4% was found for each increment of HDL-C by 1 mg/dL, and the analysis of HDL-C-quartiles demonstrated a significant risk reduction in quartile 4 relative to quartile 1 during a follow-up of 16 weeks.34 The influence of baseline HDL-C levels on outcome in the setting of ACS was still effective after 1 year, in that low HDL-C-baseline levels (<40 mg/dL in men and <45 mg/dL in women) were related to a significantly higher incidence of death, myocardial infarction, and target lesion revascularization.35 Both groups of patients (ACS in the MIRACL trial, and stable CAD in our study) may have coronary microembolization as the common cause of myocardial injury: microembolization occurs both during ACS (spontaneous plaque rupture) and PCI-related manipulations on the plaque. High-density lipoprotein may be cardioprotective via similar mechanisms in both studies: the more stable plaque morphology in patients with high HDL-C may result in a lesser and milder microembolization in case of plaque rupture, and HDL-C may additionally exert a direct cardioprotective effect. In summary, the current study strengthens the notion of the importance of HDL-C levels for cardiovascular outcome in any stage of the disease. Importantly, although HDL-C levels of <40 mg/dL (1.03 mmol/L) in men and <45 mg/dL (1.16 mmol/L) in women are currently regarded as markers of high cardiovascular risk,15 a notion supported by our findings, we would nevertheless suggest that any elevation of HDL-C regardless of actual levels may be important prior to PCI as our findings clearly show that HDL-C increments of 5 mg/dL (0.13 mmol/L; as well as 1 mg/dL, data not shown) have a profound beneficial influence on the occurrence of PMI and AMI over the whole range of HDL-C levels.

Although there are limitations of generalizing this observation as elaborated below, we consider it important to be aware that even small increases in HDL-C levels convert into cardioprotection during PCI and are therefore a worthy aim to pursue. In the present study, we observed that patients suffering from PMI were at a high risk for AMI, despite ‘low-risk HDL-C levels’ [men ≥40 mg/dL (≥1.03 mmol/L) and women ≥45 mg/dL (≥1.16 mmol/L)15]. This finding may be simply due to the fact that once myocardial injury has occurred its impact on prognosis is far stronger than any effect plasma HDL-C levels may have. It also points out how important pre-procedural HDL-C levels may be to avoid PMI and thus improve long-term prognosis of PCI. Vice versa, it also demonstrates that patients with PMI should receive particular attentive monitoring over a long period after PCI to prevent AMI, despite them having ‘low-risk HDL-C’. As the occurrence of PMI has such a significant influence on the cardiovascular outcome during the long-term follow-up, these results support the ESC recommendation of measurement of cardiac biomarkers during the first 24 h after PCI to detect PMI.7

There is ample evidence of the importance of elevated levels of C-reactive protein as predictors for the development of coronary heart disease36 and the occurrence of cardiovascular events.37 High plasma C-reactive protein correlates with vulnerable plaque morphology and plaque rupture in AMI.38,39 The reason we did not find differences in plasma C-reactive protein levels between the groups with and without PMI may lie in the different causality of myocardial damage between a spontaneous AMI and a procedure-related infarction: although AMI caused by plaque rupture is accompanied by an inflammatory process that can be monitored by C-reactive protein, the induction of injury during an elective PCI is caused by procedure-related microembolization unrelated to the actual state of vascular inflammation. A recent study supports this interpretation by demonstrating no relationship between the C-reactive protein levels and occurrence of cardiovascular events during elective PCI and the 6-month follow-up.40

We did not observe any influence of statin intake on myocardial injury (PMI or AMI), despite the known beneficial effect of statins on the risk of recurrent adverse events shown in a number of randomized trials.41 This is of no contradiction to the statin trials as the design of our study does not permit any statement on the effectiveness of pharmacologic intervention on outcome. In our study, all patients were clinically stable and the majority (76%) had been on statin medication at the time of PCI. A direct comparison of patients on statins vs. not on statins was not possible due to the limited number of patients without statins, although it is entirely possible that patients without statins (if available in a sufficient number and followed for a longer time) may have shown a worse outcome. An important question for the future is the choice of the appropriate therapy for increasing HDL levels. The known life style changes that affect HDL-C levels such as dietary intervention and physical activity may not be applicable on a short-term basis and in all patients. The drug therapy for HDL-C-elevation is based on three substance classes: statins, fibrates, and nicotinic acid. Although statins are widely used in patients with CAD to lower total and LDL-C, they show only moderate (5–15%) increase of the levels of HDL-C.41 Therapy with fibrates results in an HDL-C increase of up to 11%, whereas nicotinic acid is by far more effective as it increases HDL-C levels up to 23%.42 For all three drug classes, a significant effect on the reduction of major cardiovascular endpoints was demonstrated.43 However, a recent analysis of the effects of atorvastatin, fenofibrate, and nicotinic acid administered to patients with severe HDL-C deficiency in an intra-individual comparison design supported the clear advantage of nicotinic acid over the other two drugs in respect to raising HDL-C levels (22% compared with 6% with fenofibrate and no effect by atorvastatin).44

Limitations of the study

Our analysis is based on a collective of patients who are part of a larger cohort (n = 350 of n = 731). At the time of intervention, not all parameters of interest were collected or recorded in the total cohort, requiring the exclusion of many patients from further analysis (this is referred to in the Methods section). Although studying a subgroup population represents a limit to the message of any analysis, we deem the ‘real-life’ nature of our message too important to refrain from presenting, especially as it substantially extends previous findings in this field.34,35 Thus, any generalizations based on our findings should be made with caution and in consideration of the respective patient collectives. Nevertheless, the findings of a relationship between HDL-C, PMI, and the outcome after PMI in stable CAD patients might warrant prospective studies on this issue and become, eventually, important for the treatment of the stable CAD patients we daily see.

Conclusions

We have identified HDL-C as a clear determinant of both incidence and extent of PMI in patients undergoing elective PCI in that even small increases in HDL-C convert into a substantial reduction of risk for PMI. Future prospective studies are needed to determine whether therapeutic HDL-C elevation should be recommended prior to elective PCI for any patient. As patients suffering from PMI despite low-risk HDL-C levels are at a high risk for AMI, this patient group should receive particular attentive monitoring of the cardiovascular risk factors by the treating physician over a long period after PCI.

Funding

This work was supported by a grant from Deutsche Gesellschaft für Kardiologie—Herz- und Kreislaufforschung e.V. to K.J.E.S., a grant from the Medtronic Fellowship Program to Z.W., and by grants from Deutsche Forschungsgemeinschaft [940/4-1, LE940/3-1] to B.L.

Conflict of interest: none declared.

References

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