Conceived and designed the experiments: MK ACvdW SZR JPH RJvdS JBJ MMV MGM JJP JGPT RJdW. Performed the experiments: MK KK XL HPHMP JPH RJvdS JBJ MMV JJP RJdW. Analyzed the data: MK ACvdW JGPT RJdW. Contributed reagents/materials/analysis tools: MK ACvdW KK XL HPHMP RJdW. Wrote the paper: MK RJdW.
The authors have declared that no competing interests exist.
Plaque disruption with superimposed thrombus is the predominant mechanism responsible for the onset of acute coronary syndromes. Studies have shown that plaque disruption and thrombotic occlusion are frequently separated in time. We established the histopathological characteristics of material aspirated during primary percutaneous coronary intervention (PCI) in a large consecutive ST-elevation myocardial infarction (STEMI) population.
Thrombus aspiration during primary PCI was performed in 1,362 STEMI patients. Thrombus age was classified as fresh (<1 day), lytic (1–5 days), or organized (>5 day). Further, the presence of plaque was documented. The histopathological findings were related to the clinical, angiographic, and procedural characteristics. Material could be aspirated in 1,009 patients (74%). Components of plaque were found in 395 of these patients (39%). Fresh thrombus was found in 577 of 959 patients (60%) compared to 382 patients (40%) with lytic or organized thrombi. Distal embolization was present in 21% of patients with lytic thrombus compared to 12% and 15% of patients with fresh or organized thrombus.
Material could be obtained in 74% of STEMI patients treated with thrombus aspiration during primary PCI. In 40% of patients thrombus age is older than 24 h, indicating that plaque disruption and thrombus formation occur significantly earlier than the onset of symptoms in many patients.
Acute ST-elevation myocardial infarction (STEMI) is caused by occlusion of a coronary artery as a result of coronary atherosclerotic plaque disruption with superimposed luminal thrombus.
We recently described the composition and age of aspirated thrombi in a small cohort of STEMI patients treated with primary percutaneous coronary intervention within 6 h of onset of symptoms. We demonstrated that in approximately 50% of these STEMI patients, coronary thrombi were days or even weeks old.
Our institution is a large referral hospital with an annual PCI volume of 2,400 procedures, 600 of which are primary PCIs. Patients are eligible for primary PCI when they have symptoms of an acute STEMI accompanied by an electrocardiogram with ST-segment elevation of ≥0.2 mV in two or more contiguous leads and present within 12 hours after the onset of symptoms. PCI is performed by standard techniques through the femoral or radial route. Since August 2001, thrombus aspiration has been routinely performed when technical feasible as determined by the operator. Three different systems have been used: the 7F Rescue catheter (Boston Scientific/Scimed, Inc, Maple Grove, Minn), the 6F Export aspiration catheter (Medtronic Vascular Incorporation, Santa Rosa, CA), and the 6/7F Proxis™ embolic protection device (St. Jude Medical, St. Paul, MN). The choice of the aspiration device is at the discretion of the operator. Pharmacologic treatment before PCI includes the administration of aspirin in a loading dose of 300 mg, unfractionated heparin 5,000–10,000 IU, and clopidogrel in a loading dose of 300 or 600 mg. The use of glycoprotein IIb/IIIa inhibitors and anti-thrombotic medications is at the discretion of the operator. Clinical, angiographic, and procedural characteristics of all PCI-procedures are prospectively collected in an electronic database.
The study cohort consists of all patients in whom thrombus aspiration was performed in adjunct to the conventional primary PCI between August 2001 and January 2008.
Information about baseline characteristics (gender, patient age, risk factors, cardiac history, medication, etc.), procedural characteristics, angiographic characteristics (lesion length, bifurcation, chronic total occlusion, stent implantation, procedural success), and the use of thrombus aspiration devices (type of device, device passage, angiographic result, material obtained) was obtained from the electronic database. Angiographic characteristics such as distal embolization, pre- and post-procedural TIMI flow, lesion length, and residual stenosis have been prospectively recorded by the operator by visual assessment immediately after the procedure. In this study informed patient consent was not acquired, because thrombus aspiration and the histopathological assessment of aspirated material were part of routine clinical practice. In addition, because of the study being part of routine clinical practice nor a formal waiver under the description of Record-based Research from or approval by the local Medical Ethical Committee were required for this study.
Aspirated material was fixed in formalin immediately after thrombus aspiration and was sent to the department of cardiovascular pathology. Material was fixed for at least 24 hours in 10% neutral buffered formalin and embedded in paraffin. The paraffin embedded material was serially sectioned, cut, and mounted on glass slides at ≥6 levels. The sections were stained with Hematoxylin and Eosin (H&E) for light microscopy. Histopathological analyses were performed by an experienced cardiovascular pathologist (A vd W) while blinded to the clinical characteristics of the patients, angiographic findings, and the result of the PCI-procedure. The sections were analysed for the presence or absence of aspirated material. If sufficient material was available (≥1 mm2) and thrombus was present, thrombus age was classified into 3 groups according to previously published and histopathologically accepted definitions.
Continuous data were expressed as mean±standard deviation and categorical data as frequencies, unless otherwise noted. Differences between patient groups were tested with Student's
Mechanical thrombus aspiration during primary PCI was performed in 1,362 patients. Histopathologically confirmed material was obtained in 1,009 patients (74%). In the remaining 353 patients (26%) material could not be identified (
Clinical, angiographic and procedural characteristics of the patients with and without histopathologically confirmed material are summarized in
Material obtained | No material obtained | P value | |
(n = 1,009) | (n = 353) | ||
Male | 748 (74) | 247 (70) | 0.14 |
Age (years) | 59±13 | 62±12 | 0.001 |
Diabetes mellitus | 100 (10) | 34 (10) | 0.92 |
Hypercholesterolaemia | 205 (20) | 76 (22) | 0.65 |
Current smoking | 496 (49) | 163 (46) | 0.35 |
Hypertension | 313 (31) | 111 (31) | 0.89 |
Previous MI | 90 (9) | 33 (9) | 0.83 |
Previous CABG) | 17 (2) | 4 (1) | 0.62 |
Previous PCI | 64 (6) | 21 (6) | 0.90 |
Shock | 118 (12) | 37 (11) | 0.56 |
Total ischemic time (h)† | 3.7±3.4 | 3.8±3.2 | 0.32 |
Infarct related artery LAD | 436 (43) | 143 (41) | 0.38 |
Pre-procedural TIMI flow 0–1§ | 846 (85) | 290 (84) | 0.49 |
Multivessel disease§ | 283 (27) | 96 (28) | 0.78 |
Lesion type class C‡§ | 353 (37) | 127 (40) | 0.42 |
Bifurcation§ | 91 (9) | 46 (13) | 0.04 |
Ostial§ | 74 (7) | 20 (6) | 0.33 |
Calcified§ | 143 (14) | 68 (19) | 0.03 |
Lesion length (mm)§ | 16.6±6.2 | 15.4±5.8 | <0.0001 |
Stent placement | 937 (93) | 326 (92) | 0.72 |
Stent length (mm) | 19.3±5.3 | 18.3±4.8 | 0.03 |
Stent diameter (mm) | 3.6±0.5 | 3.4±0.5 | <0.0001 |
Post-procedural TIMI flow 3§ | 898 (90) | 314 (91) | 0.67 |
Residual stenosis ≥20%§ | 35 (4) | 14 (4) | 0.62 |
Distal embolization§ | 147 (15) | 27 (7) | 0.001 |
Continous variables are presented as means and standard deviations and categorical data are presented as frequencies (counts) and percentages.
LAD = left anterior descending coronary artery; TIMI = Thrombolysis In Myocardial Infarction; § = By visual assessment by the operator; † = Time between onset of symptoms and needle time; ‡ = According to the ACC-AHA classification.
Univariate analysis showed a significant association between the presence of aspirated material and patient age, bifurcated lesions, and calcified lesions. Multivariate analysis identified patient age (0.65 [95% CI 0.51 to 0.83], p = 0.001) and occlusion of a bifurcation lesion (0.65 [95% CI 0.44 to 0.95], p = 0.024) as independent predictors of the presence of aspirated material (data not shown).
Thrombus could not be identified or thrombus could not be classified according to age, in 50 of the 1,009 patients with aspirated material. These patients were excluded from the analysis (
Thrombus age | Patients | Subcategory thrombus age | Patients |
(n = 959) | (n = 959) | ||
Fresh thrombus | 577 (60) | ||
Lytic thrombus | 199 (21) | Complete lytic thrombus | 131 (66) |
Fresh and lytic thrombus | 68 (34) | ||
Organized thrombus | 183 (19) | Complete organized thrombus | 68 (37) |
Fresh and organized thrombus | 44 (24) | ||
Lytic and organized thrombus | 40 (22) | ||
Fresh, lytic and organized thrombus | 31 (17) |
The categorical data are presented as frequencies (counts) and percentages.
Clinical, procedural, and angiographic characteristics of the patients with fresh, lytic or organized thrombus are summarized in
Fresh thrombus | Lytic thrombus | Organized thrombus | P value | |
(n = 577) | (n = 198) | (n = 183) | ||
Male | 439 (76) | 142 (72) | 132 (72) | 0.32 |
Age (years) | 59±13 | 61±13 | 58±14 | 0.07 |
Diabetes mellitus | 58 (10) | 20 (10) | 14 (8) | 0.60 |
Hypercholesterolaemia | 117 (20) | 43 (22) | 35 (19) | 0.81 |
Current smoking | 288 (50) | 98 (50) | 93 (51) | 0.98 |
Hypertension | 192 (33) | 60 (30) | 50 (27) | 0.28 |
Previous MI | 43 (8) | 23 (12) | 15 (8) | 0.19 |
Previous CABG | 9 (2) | 6 (3) | 0 (0) | 0.06 |
Previous PCI | 39 (7) | 13 (7) | 10 (5) | 0.82 |
Shock | 64 (11) | 23 (12) | 27 (15) | 0.42 |
Total ischemic time (h)† | 3.3±2.4 | 4.0±4.3 | 4.2±4.4 | 0.007 |
Infarct related artery LAD | 252 (44) | 82 (41) | 77 (42) | 0.82 |
Pre-procedural TIMI flow 0–1§ | 488 (86) | 166 (86) | 153 (85) | 0.99 |
Multivessel disease§ | 167 (29) | 46 (23) | 52 (28) | 0.29 |
Lesion type class C‡§ | 205 (37) | 69 (37) | 60 (35) | 0.90 |
Bifurcation§ | 54 (9) | 16 (8) | 16 (9) | 0.85 |
Ostial§ | 39 (7) | 16 (8) | 18 (10) | 0.39 |
Calcified§ | 89 (15) | 28 (14) | 18 (10) | 0.21 |
Lesion length (mm)§ | 16.5±6.5 | 17.0±5.6 | 16.6±6.1 | 0.61 |
Stent placement | 539 (93) | 177 (89) | 175 (95) | 0.07 |
Stent length (mm) | 19.1±4.8 | 19.5±5.8 | 19.7±5.8 | 0.98 |
Stent diameter (mm) | 3.6±0.5 | 3.6±0.5 | 3.5±0.5 | 0.10 |
Post-procedural TIMI flow 3§ | 524 (92) | 173 (88) | 160 (88) | 0.12 |
Residual stenosis ≥20%§ | 18 (3) | 11 (6) | 4 (2) | 0.14 |
Distal embolization§ | 70 (12) | 42 (21) | 28 (15) | 0.007 |
Continous variables are presented as means and standard deviations and categorical data are presented as frequencies (counts) and percentages.
LAD = left anterior descending coronary artery; TIMI = Thrombolysis In Myocardial Infarction; § = By visual assessment by the operator; † = Time between onset of symptoms and needle time; ‡ = According to the ACC-AHA classification.
Univariate analysis showed a significant association between the age of aspirated thrombus and total ischemic time. Multivariate analysis identified a history of hypertension (1.31 [95% CI 0.98 to 1.75], p = 0.072) and a longer total ischemic time (1.08 [95% CI 1.03 to 1.13], p = 0.001) as independent predictors for the presence of older thrombus (lytic or organized) (data not shown).
Components of plaque were found in 396 of the 1,009 patients (39%) with aspirated material. In 31 patients (3%) aspirated material consists of only plaque components. Both thrombus and plaque components could be identified in 365 patients (36%). In the majority of the patients components of soft plaque were found (339/395, 86%). Histological evidence of calcific deposits and fibrous or fibro-elastic tissue was found in 105 (27%) and 104 patients (26%), respectively.
In this study we report the histopathological characteristics of material obtained from a large consecutive cohort of STEMI patients treated with thrombus aspiration in adjunct to conventional primary PCI. Aspirated material could histopathologically be confirmed in 74% of the patients. The obtained thrombus material showed lytic or organized changes in 40% of the patients, indicating the thrombus is older than 24 hours in a significant proportion of STEMI patients with onset of symptoms less than 12 hours before.
We found older thrombus (more than one day) in a substantial proportion of the STEMI patients (40%) and the composition of the these thrombi was often heterogeneous, showing in part features of fresh, of lytic, and organized thrombus. These results support the concept of coronary artery disease as a dynamic process. Disruption of atherosclerotic plaques may act as a stimulus for repeated or ongoing thrombosis, which ultimately progresses over a period of days or even weeks to thrombotic occlusion with a secondary fresh thrombus. Systematic histopathological analyses of the atherothrombotic material obtained with thrombus aspiration during primary PCI in large patient cohorts are limited. Our findings are in line with our previous results that describe histopathological analyses of aspirated atherothrombotic material in a smaller group of 211 STEMI patients in whom we identified older thrombus in approximately 50% of patients.
In our study we aspirated atherothrombotic material in almost three-quarter of the patients in whom an aspiration device was used in adjunct to the conventional primary PCI. This is similar to the 73% rate of histopatholgically confirmed material in the EMERALD trial, the 73% rate in the TAPAS trial, and the 77% rate with the use of the Proxis™ embolic protection device.
Except for the TAPAS study, previous studies with thrombus aspiration have been neutral or negative. Therefore, the use of a thrombus aspiration device was non-standard clinical practice during the study period and the decision to perform thrombus aspiration was at the discretion of the operator. In some patients, thrombus aspiration was not possible depending on coronary anatomy, and in 353 patients no material was obtained. However, we believe that there was no systemic selection of patients that could influence our conclusions. Secondly, we cannot exclude the possibility that atherothrombotic material was selectively aspirated from the total of atherothrombotic material in situ. In our view, this cannot be the sole explanation for the observed histopathological features of the aspirated thrombus. Thirdly, additional immunostaining to optimize visualization of smooth muscle cells in specimen of lytic or organized thrombus was not performed. The major distinction in our paper, though, is fresh versus lytic or organized thrombus, which is not affected by this limitation. Finally, full information regarding anginal symptoms in the days or weeks before the acute myocardial infarction was not available. However, our previous thrombectomy study showed no clear relation between thrombus age and the presence or absence of preinfarction angina.
Our study shows that histopathologically confirmed material could be obtained in almost three-quarter of a large consecutive cohort of STEMI patients treated with thrombus aspiration during primary PCI. Forty percent of the aspirated material showed features of thrombus formation that occurred several days or even weeks earlier, which confirms that there is an unpredictable time span between onset of plaque disruption, thrombus formation, and the onset of clinical symptoms of acute myocardial infarction. In addition, our data suggest that there is a time window of several days after plaque disruption in which thrombus embolization is most likely. Knowledge of the composition and age of the thrombus, perhaps with non-invasive imaging, might be helpful in the future for the planning and choice of adjuvant therapy during primary PCI.