Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, has recently been linked to atherosclerosis and development of postinfarction heart failure. This study was designed to assess the association between admission OPG levels and microvascular obstruction (MVO) in patients who underwent primary percutaneous coronary intervention (p-PCI). Plasma samples for OPG analysis were obtained <30 minutes after admission in 47 patients who underwent p-PCI. Angiographic no-reflow (Thrombolysis In Myocardial Infarction [TIMI] flow grade <3 or 3 with myocardial blush grade 0 or 1 after p-PCI) was assessed immediately after p-PCI. MVO was assessed and quantified by the intracoronary hemodynamic measure of index of microcirculatory resistance performed on day 4 or 5 after p-PCI. Patients with angiographic no-reflow had significantly higher OPG levels on admission. On multiple linear regression analysis, OPG (β = 0.412, p = 0.001) and B-type natriuretic peptide (β = 0.409, p = 0.001) levels were independently and directly associated with the index of microcirculatory resistance. In conclusion, plasma OPG levels on admission are strongly associated with MVO and significantly correlated with the degree of MVO after p-PCI. It remains to be established whether improvement of microvascular perfusion is feasible with therapeutic strategies aimed to decrease circulating OPG levels.
Despite the successful restoration of normal epicardial flow, myocardial perfusion remains impaired in as many as 50% of patients with ST-segment elevation myocardial infarction (MI), a condition known as “no-reflow phenomenon” or microvascular obstruction (MVO). The prognostic value of the presence and the extent of MVO in patients after MI has been well demonstrated in previous studies. Thus, the identification of new tools for risk stratification to select patients at high risk for the no-reflow phenomenon is important. Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, acts as a decoy receptor for receptor activator of nuclear factor κB ligand (RANKL) and interferes in its binding to cell surface receptor activator of nuclear factor κB (RANK). Besides its important regulatory role in bone metabolism, endocrine function, and the immune system, the OPG–RANKL–RANK axis has also been linked to atherosclerosis. Despite the established link between the increased OPG levels and myocardial failure in post-MI patients, whether OPG plays an independent pathophysiologic role in the progression of heart failure or is merely a marker of the severity of ventricular dysfunction has not been clearly defined. We hypothesized that circulating OPG levels on admission are associated with reperfusion injury and MVO after primary percutaneous coronary intervention (p-PCI). To test this hypothesis, we measured OPG in plasma samples and used standard methods and intracoronary hemodynamic measures to assess microvascular perfusion in patients who underwent p-PCI.
Methods
Forty-seven patients with their first acute ST-segment elevation MIs who were admitted to Kartal Kosuyolu Heart Education and Research Hospital and scheduled to undergo p-PCI <12 hours after the onset of symptoms were prospectively enrolled. Inclusion criteria were (1) typical ongoing ischemic chest pain for >30 minutes and (2) ST-segment elevation ≥0.1 mV in ≥2 contiguous leads or new left bundle branch block on initial electrocardiograph. Exclusion criteria were cardiogenic shock and/or clinical instability, previous ST-segment elevation MI, malignant life-threatening diseases, the presence of an additional lesion causing >50% narrowing distal to the culprit lesion, peripheral arterial disease, aortic aneurysm, chronic inflammatory disease, and renal failure. Preinfarction angina pectoris was defined as cardiac symptoms for <30 minutes that occurred <2 days before infarct onset.
All patients received chewable aspirin 300 mg and a loading dose of clopidogrel 600 mg on admission to the emergency room. Written informed consent was obtained from all patients. The study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by our hospital ethics committee.
All p-PCI procedures were performed by experienced interventional cardiologists through a femoral approach with a 7Fr guiding catheter. An intravenous bolus of unfractionated heparin at a dose of 70 U/kg body weight was administered. All patients received tirofiban as a glycoprotein IIb/IIIa inhibitor. Thrombus aspiration was recommended depending on relevant thrombus. In all patients, balloon predilatation was followed by stent implantation. Those patients with additional lesions causing >50% narrowing distal to the culprit lesion were excluded after angiography. All patients were treated with maintenance doses of clopidogrel (75 mg/day for 12 months) and aspirin (300 mg for 30 days and then 100 mg indefinitely). Other guideline-based cardiac medications were administered at the maximum tolerated doses.
Angiographic analysis included pre- and postprocedural Thrombolysis In Myocardial Infarction (TIMI) flow grade, corrected TIMI frame count, and myocardial blush grade. Visual assessments were performed offline by 2 blinded observers. Angiographic no-reflow was defined as TIMI flow grade < 3 or 3 with a myocardial blush grade of 0 or 1.
All echocardiographic studies were performed and interpreted on the third day after MI by 2 experienced blinded sonographers. The left ventricular ejection fraction and wall motion score index were measured according to American Society of Echocardiography criteria.
For OPG plasma level measurement, venous peripheral blood samples were drawn on admission, before the administration of any medication. Pyrogen-free blood collection tubes, with ethylenediaminetetraacetic acid as an anticoagulant, were centrifuged within 30 minutes (2,000 rpm for 10 minutes). Plasma was separated, aliquoted, and frozen at −80°C until analysis. Plasma OPG was quantified in duplicate by using a commercially available in vitro enzyme-linked immunosorbent assay (RayBiotech, Norcross, Georgia) according to the manufacturer’s instructions. The intra-assay coefficient of variation was 4.1%. The lower limit of detection was 1 pg/ml.
Plasma B-type natriuretic peptide (ADVIA Centaur B-type natriuretic peptide assay; Bayer Diagnostics, Tarrytown, New York) and serum C-reactive protein (IMMAGE nephelometer; Beckman Coulter, Inc., Fullerton, California) levels were measured <1 hour after blood collection. Other biochemical and hemographic parameters were determined by our routine laboratory methods.
Four to 5 days after p-PCI, all patients underwent repeat cardiac catheterization. For hemodynamic measurements, a guidewire tipped with pressure and temperature sensors (PressureWire 5 Sensor; Radi Medical Systems, Uppsala, Sweden) was positioned distal to the stented segment of the infarct-related artery. Intravenous adenosine (140 μg/kg/min) was used as the hyperemic agent. The hemodynamic measurements were performed, as previously described, by an independent and blinded interventionalist different from the one who performed p-PCI. Thermodilution-derived coronary flow reserve was calculated as the mean transit time at rest divided by the mean transit time during hyperemia. The index of microcirculatory resistance (IMR) was calculated by dividing the mean distal coronary pressure by the inverse of mean hyperemic transit time (multiplication of distal coronary pressure and mean hyperemic transit time).
The Kolmogorov-Smirnov test was used to test the normality of distribution of continuous variables. Continuous variables with normal and non-normal distributions are expressed as mean ± SD and median (interquartile range), respectively. Categorical variables are expressed as numbers and percentages of patients. Group means for continuous variables with normal and non-normal distributions were compared using Student’s t tests and Mann-Whitney U tests, respectively. Categorical variables were compared using chi-square tests or Fischer’s exact tests, as appropriate. Finally, a multiple linear regression analysis was conducted using the IMR as the dependent variable to assess the relation between the OPG levels and the degree of MVO.
Results
The study population consisted of 47 patients (89% men, mean age 56 ± 7.7 years, range 39 to 73) with ST-segment elevation MI who underwent p-PCI. Blood samples were obtained <30 minutes after admission, before the administration of any medication. The mean time from symptom onset to blood collection was 165 ± 94 minutes. The mean plasma OPG level was 114 ± 105 pg/ml, with a median value of 81 pg/ml. The baseline clinical characteristics of the subgroups of patients, with OPG levels higher and lower than the median, were comparable ( Table 1 ). There was no significant correlation between OPG levels and baseline characteristics, except for weak correlations between OPG and age (r = 0.32 p = 0.027), B-type natriuretic peptide (r = 0.298, p = 0.04), and C-reactive protein (r = 0.38, p = 0.04).
| Characteristic | All Patients (n = 47) | OPG < Median (n = 24) | OPG > Median (n = 23) | p Value |
|---|---|---|---|---|
| Main characteristics | ||||
| Age (years) | 56 ± 7.7 | 55 ± 6.4 | 57 ± 8.8 | 0.28 |
| Body mass index (kg/m 2 ) | 27 ± 4.4 | 27 ± 5.3 | 26 ± 3.5 | 0.59 |
| Men | 42 (89%) | 22 (92%) | 20 (87%) | 0.67 |
| Diabetes mellitus | 7 (15%) | 4 (17%) | 3 (13%) | 1.00 |
| Hypertension ⁎ | 13 (28%) | 6 (25%) | 7 (30%) | 0.75 |
| Hypercholesterolemia † | 4 (8.5%) | 2 (8.3%) | 2 (8.7%) | 1.00 |
| Current smoker | 35 (75%) | 19 (79%) | 16 (70%) | 0.52 |
| Preinfarction angina pectoris | 28 (60%) | 12 (52%) | 16 (70%) | 0.24 |
| Systolic blood pressure (mm Hg) | 131 ± 26 | 132 ± 24 | 130 ± 28 | 0.75 |
| Diastolic blood pressure (mm Hg) | 81 ± 18 | 83 ± 18 | 80 ± 19 | 0.56 |
| Heart rate (beats/min) | 77 ± 16 | 80 ± 18 | 74 ± 14 | 0.19 |
| Anterior MI | 29 (62%) | 16 (67%) | 13 (57%) | 0.56 |
| Killip class ≥II | 7 (15%) | 3 (13%) | 4 (17%) | 0.70 |
| Initial ST elevation (mm) | 11 ± 8 | 13 ± 8 | 10 ± 7 | 0.21 |
| Wall motion score index | 1.29 ± 0.17 | 1.3 ± 0.18 | 1.28 ± 0.16 | 0.61 |
| Left ventricular ejection fraction (%) | 54 ± 7.8 | 53 ± 7.5 | 54 ± 8.2 | 0.56 |
| Medications | ||||
| Aspirin | 47 (100%) | 24 (100%) | 23 (100%) | 1.00 |
| Clopidogrel | 47 (100%) | 24 (100%) | 23 (100%) | 1.00 |
| Enoxaparin | 47 (100%) | 24 (100%) | 23 (100%) | 1.00 |
| β blockers | 42 (89%) | 22 (92%) | 20 (87%) | 0.67 |
| Statins | 43 (92%) | 23 (96%) | 20 (87%) | 0.35 |
| Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers | 37 (79%) | 19 (79%) | 18 (78%) | 1.00 |
| Intravenous tirofiban | 47 (100%) | 24 (100%) | 23 (100%) | 1.00 |
| Intracoronary tirofiban | 24 (51%) | 12 (50%) | 12 (52%) | 1.00 |
| Laboratory tests | ||||
| Peak troponin I (pg/ml) | 67 ± 53 | 69 ± 50 | 65 ± 57 | 0.82 |
| B-type natriuretic peptide (pg/ml) | 85 ± 94 | 79 ± 78 | 92 ± 109 | 0.64 |
| C-reactive protein (mg/dl) | 0.6 ± 0.5 | 0.5 ± 0.3 | 0.7 ± 0.6 | 0.32 |
| Hemoglobin (g/dl) | 14 ± 1.5 | 14 ± 1.3 | 14 ± 1.8 | 0.66 |
| Neutrophil count (×10 9 /L) | 8.1 ± 2.5 | 8.2 ± 2.4 | 8 ± 2.6 | 0.74 |
| Platelet count (×10 9 /L) | 261 ± 60 | 253 ± 53 | 270 ± 67 | 0.35 |
⁎ Systolic blood pressure >140 mm Hg and/or diastolic blood pressure >90 mm Hg or receiving antihypertensive treatment.
† Total cholesterol >200 mg/dl and/or low-density lipoprotein cholesterol >130 mg/dl or receiving lipid-lowering therapy.
Angiographic characteristics and procedural results for the 2 groups were comparable ( Table 2 ). Time from symptom onset to p-PCI was 201 ± 98 minutes. P-PCI was successful in all patients. Each patient received ≥1 stent. Most patients achieved TIMI grade 3 flow (87%). The incidence of angiographic no-reflow was 36%.
| Characteristic | All Patients (n = 47) | OPG < Median (n = 24) | OPG > Median (n = 23) | p Value |
|---|---|---|---|---|
| Preprocedural characteristics | ||||
| Pain to balloon time (minutes) | 201 ± 98 | 200 ± 94 | 202 ± 105 | 0.92 |
| Culprit left anterior descending coronary artery | 28 (60%) | 15 (63%) | 13 (57%) | 0.77 |
| Multivessel disease | 36 (77%) | 21 (88%) | 15 (65%) | 0.09 |
| Baseline TIMI grade 0 or 1 | 47 (100%) | 24 (100%) | 23 (100%) | 1.00 |
| Thrombus score 4 or 5 | 47 (100%) | 24 (100%) | 23 (100%) | 1.00 |
| Number of stents | 1.23 ± 0.47 | 1.16 ± 0.38 | 1.3 ± 0.56 | 0.40 |
| Maximal inflation pressure (atm) | 16 (14–18) | 16 (14–18) | 16 (14–18) | 0.31 |
| Length of stent (mm) | 25 (20–28) | 22.5 (18–28) | 25 (20–32) | 0.47 |
| Use of thrombus aspirating device | 6 (13%) | 3 (13%) | 3 (13%) | 1.00 |
| Minimal luminal diameter (mm) | 3 ± 0.31 | 3 ± 0.33 | 3.1 ± 0.27 | 0.24 |
| Mean residual stenosis (%) | 8.7 ± 5.5 | 9.8 ± 6.1 | 7.5 ± 4.6 | 0.20 |
| Side branch embolization | 6 (13%) | 4 (17%) | 2 (8.7%) | 0.67 |
| Postprocedural results | ||||
| TIMI flow grade | 0.09 | |||
| 2 | 6 (13%) | 1 (4%) | 5 (22%) | |
| 3 | 41 (87%) | 23 (96%) | 18 (78%) | |
| Corrected TIMI frame count | 23 ± 9 | 20 ± 5 | 25 ± 11 | 0.04 |
| Myocardial blush grade | 0.01 | |||
| 0 or 1 | 16 (34%) | 4 (17%) | 12 (52%) | |
| 2 or 3 | 31 (66%) | 20 (83%) | 11 (48%) | |
| Angiographic no-reflow | 17 (36%) | 5 (21%) | 12 (52%) | 0.036 |
| Second catheterization | ||||
| IMR >30 U | 23 (49%) | 7 (29%) | 16 (70%) | 0.009 |
| IMR (U) | 31 ± 14 | 26 ± 13 | 36 ± 14 | 0.013 |
| Coronary flow reserve | 2.1 ± 0.7 | 2.2 ± 0.7 | 1.9 ± 0.6 | 0.18 |
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