Abstract
Introduction
Near-infrared spectroscopy (NIRS) is a new method to identify lipid core plaque (LCP). The LCP and vascular response were assessed with NIRS to examine whether LCP was compressed or redistributed during percutaneous coronary intervention with stent implantation.
Methods
In 25 patients with non-ST segment elevation myocardial infarction (NSTEMI) NIRS acquisition was performed after predilation, stent implantation with nominal pressure and high-pressure post-dilation with a non-compliant balloon. The intravascular ultrasound (IVUS) measures included volumes of external elastic membrane (EEM), lumen and plaque + media. The NIRS measures included lipid core burden index (LCBI) and maximum value of LCBI for any of the 4-mm segment (maxLCBI 4mm ).
Results
From predilation to stent implantation and post-dilation EEM volume increased from 337 ± 124 mm 3 to 369 ± 136 mm 3 and to 397 ± 144 mm 3 (p < 0.001), while plaque volume decreased from 225 ± 84 mm 3 to 202 ± 85 mm 3 and to 192 ± 81 mm 3 (p < 0.001). Plaque shift to the proximal reference segment was found in 40% of the lesions. The maxLCBI 4mm decreased significantly from predilation to stent implantation (492 ± 235 to 208 ± 193 (p < 0.001), whereas post dilation did not cause any further significant reduction. Also LCBI decreased significantly from predilation to stent implantation (173 ± 103 to 68 ± 67, p < 0.001), without any further significant reduction during post-dilation. The LCBI did neither in the proximal nor in the distal reference segments change significantly during stent implantation or post-dilation.
Conclusion
Lumen enlargement was caused by vessel expansion, plaque compression and longitudinally plaque redistribution. Lipid-core burden at the stented segment was decreased.
Highlights
- •
Acute coronary syndromes mainly develop from rupture of a vulnerable.
- •
Vulnerable plaques have a thin fibrotic cap and a lipid-rich necrotic core that is highly thrombogenic.
- •
The lipid-core plaque can be identified and quantified in vivo by near-infrared spectroscopy.
- •
During percutaneous coronary intervention the lipid-core plaque may be compressed or redistributed longitudinally.
1
Introduction
Acute coronary syndromes (ACSs) mainly develop from rupture of a vulnerable plaque which may result in a sudden luminal thrombosis formation . Vulnerable plaques have thin fibrotic cap and lipid-rich necrotic core that is highly thrombogenic . Percutaneous coronary intervention (PCI) of these extensive lipid rich plaques may be associated with an increased risk of short and long-term complications. Slow or no-reflow phenomenon and periprocedural myocardial infarction are mainly due to distal embolization of intraluminal thrombus during coronary intervention of lipid-core plaque (LCP) . Additionally, stent failure defined as stent thrombosis or re-stenosis can occur in segments with LCP especially if stent edges are embedded in lipid-rich plaques .
Near-infrared spectroscopy (NIRS) is a novel coronary imaging technique validated against autopsy material, and is an excellent tool for in vivo identification and evaluation of LCP . Patients with ACS have higher incidence of lesions composed of LCP, compared to patients with stable angina . Recently it has been shown that more than half of the patients with non-ST myocardial infarction (NSTEMI) have a large LCP at the culprit lesion . Furthermore intravascular ultrasound (IVUS) studies have demonstrated a greater reduction in plaque volume in patients with ACS compared to patients with stable angina, as a mechanism of lumen enlargement during PCI .
The present study used NIRS to investigate changes in LCP and plaque volume in patients with NSTEMI treated with PCI and stent implantation, where the vessel wall was assessed after predilation, stent implantation with nominal pressure and post-dilation with a non-compliant balloon; focusing on whether LCP is being compressed or redistributed longitudinally during balloon angioplasty and stent implantation.
2
Methods
2.1
Study population
This study was conducted in patients with NSTEMI fulfilling criteria for myocardial infarction by the universal definition , and referred for invasive coronary angiography (CAG) and PCI at Department of Cardiology, Odense University Hospital (Odense, Denmark). Patients aged 18–80 were included in the study if (1) CAG demonstrated a de novo native coronary artery lesion, which was treated with a drug eluting stent (DES), and (2) NIRS-IVUS imaging was performed after predilation, stent implantation and post-dilation with an non-compliant balloon. Patients were excluded if (1) they participated in other randomized trials, (2) life expectancy <1 year, (3) allergy to aspirin, clopidogrel, ticagrelor or prasugrel, (4) s-creatinine >150 μmol/L, (4) tortuous and extremely calcified lesions, (5) lesion was near a side branch >1.5 mm in diameter with possibility of plaque shift , (6) left main lesion or long lesions requiring treatment with two stents, (7) lesion in a reference vessel diameter < 2.5 mm and (8) hemodynamic instability.
The study protocol was approved by The Regional Scientific Ethical Committees for Southern Denmark (S-20130175) and Danish Data Protection Agency (14/8158). Written informed consent was obtained from all patients before the procedure.
2.2
Invasive coronary angiography and NIRS/IVUS imaging of the culprit lesion
CAG was performed according to standard technique using the femoral approach. Culprit lesion was defined as a lesion ≥70% diameter stenosis visually assessed by the physician who performed the angiogram. If the patient had several significant stenoses and the culprit lesion was difficult to identify; right coronary artery (RCA), left anterior descending coronary artery (LAD) and left circumflex coronary artery (Cx) were chosen in the mentioned order.
To facilitate NIRS-IVUS catheter passage, a 2.0 mm balloon was inflated to minimize alteration of LCP while still achieving vessel patency. After administration of 100–200 μg intracoronary nitroglycerine, NIRS-IVUS catheter (TVC Imaging System, Infraredx, Burlington, MA) with IVUS frequency of 40 MHz was advanced over a BMW guide wire to a reference point of at least 5 mm distal to the culprit lesion. With an automated rotational pullback at a speed of 0.5 mm/s and 240 rpm the scanning was stopped when entering the guiding catheter or when a satisfying length of proximal reference segment was archived. Overall 3 pullbacks of each culprit lesion were acquired: after predilation, after stent implantation with nominal pressure at 11 atm for Synergy™ stent and lastly after post-dilation with a non-compliant balloon 0.5 mm larger than the chosen stent diameter. Immediately after pullback, data were displayed on the screen allowing the physician to precisely measure length of stenosis and choose an appropriate stent diameter using longitudinal and cross-sectional IVUS view together with a chemogram map. After the procedure the NIRS and IVUS images were recorded to a compact disk for quantitative analysis offline.
All of the lesions were treated with one single DES Synergy™ (Boston Scientific). The platinum chromium platform and a stent strut thickness of 74 μm increase the stent flexibility, but to avoid longitudinal stent deformation it has additional end connectors to increase the longitudinal robustness .
2.3
NIRS system
The near-infrared spectroscopy performs more than 30,000 chemical measurements per 100 mm of artery scanned through the blood, and each measurement interrogates 1–2 mm 2 of tissue at a depth of about 1 mm. The catheter can distinguish between different chemical compositions and identifies LCP based on different absorption pattern of each substance . The probability of LCP in the scanned vessel is then displayed in a chemogram, where x-axis is millimeters of pullback (0–120 mm), and y-axis is the catheter rotation (0°–360°) with red indicating a low probability and yellow indicating a probability >0.6 of LCP. Lipid-core burden index (LCBI) is a summary measure of the amount of LCP along the entire interrogated length of the vessel on a 0–1000 scale, while the maxLCBI 4mm is a segment with the maximum value of LCBI in a 4 mm segment. The block chemogram summarizes the chemogram in 2 mm length and 4 probabilities corresponding to the possibility (P) of LCP: red P < 0.57, orange 0.57 ≤ P ≤ 0.84, tan 0.84 ≤ P ≤ 0.98, yellow P > 0.98.
2.4
Offline analysis
Pre-intervention measurements of reference vessel diameter, minimum lumen diameter, degree stenosis and lesion length were accessed visually from CAG by the physician who performed the angiogram. Offline NIRS-IVUS analyses were performed using CAAS IntraVascular Software (Pie Medical Imaging, Maastricht, The Netherlands). All IVUS measurements were performed in accordance with the standards of American College of Cardiology and the European Society of Cardiology . Before performing the analyses reproducible landmarks such as side branches and calcium deposits were identified in each of the three pullbacks, resulting in exactly identical segments. The reference segments were 5 mm proximally and distally to the lesion (corresponding to the stented area). Overall analysis was lesion plus reference segments. At each 1 mm the cross-sectional area (CSA) of lumen, external elastic membrane (EEM) and plaque + media (EEM CSA − lumen CSA) were analyzed, and volumes were calculated using the Simpson’s rule by the software. The lesion (corresponding to the stent covered segment) was divided into three equal parts (proximal, mid and distal zone). A significant plaque shift in reference segments was identified as >1 mm 3 /mm increase in plaque volume index from predilation to post-dilation. Volume index defined as volume/lesion length (mean CSA) was also calculated due to the different lesion lengths. Stent malapposition was defined as ≥1 stent strut clearly separated from the intimal surface of the vessel wall with evidence of blood speckling behind the stent strut without overlapping a side branch. The remodeling index was defined as a ratio of (lesion/average reference) EEM area. Positive remodeling was defined as a remodeling index >1.05 and negative remodeling as a remodeling index <0.95.
From the NIRS acquisitions, the following measurements were performed: LCBI, maxLCBI 4mm , LCBI per length of the scanned artery (LCBI/L), the greatest angular extent of lipid-core plaque (0°–360°) from the cross-sectional view and length of LCP measured from block chemogram defined as yellow and/or tan blocks not interrupted by orange or red blocks. LCP compressed behind the stent is defined as LCBI ≥50 (lesion) after post-dilation. The study population divided into two groups: lesion with a large LCP (maxLCBI 4mm ≥ 500) and without (maxLCBI 4mm < 500).
2.5
Statistical analysis
Statistical analysis was performed using SPSS 22. Categorical variables were presented as counts and percentages, and group comparisons were made using chi-square test or Fisher’s exact test. Normally distributed continuous variables were displayed as mean ± SD, and compared using 2-tailed paired and unpaired t tests. If data were not normally distributed, Mann–Whitney U test or Wilcoxon signed-rank test was used instead. Correlations between variables were described with the use of Pearson correlation coefficient. P value <0.05 was considered statistically significant. The intra-observer variation evaluating the reproducibility of IVUS analyses was evaluated by re-measuring 10 lesions and calculating the percentage difference.
2
Methods
2.1
Study population
This study was conducted in patients with NSTEMI fulfilling criteria for myocardial infarction by the universal definition , and referred for invasive coronary angiography (CAG) and PCI at Department of Cardiology, Odense University Hospital (Odense, Denmark). Patients aged 18–80 were included in the study if (1) CAG demonstrated a de novo native coronary artery lesion, which was treated with a drug eluting stent (DES), and (2) NIRS-IVUS imaging was performed after predilation, stent implantation and post-dilation with an non-compliant balloon. Patients were excluded if (1) they participated in other randomized trials, (2) life expectancy <1 year, (3) allergy to aspirin, clopidogrel, ticagrelor or prasugrel, (4) s-creatinine >150 μmol/L, (4) tortuous and extremely calcified lesions, (5) lesion was near a side branch >1.5 mm in diameter with possibility of plaque shift , (6) left main lesion or long lesions requiring treatment with two stents, (7) lesion in a reference vessel diameter < 2.5 mm and (8) hemodynamic instability.
The study protocol was approved by The Regional Scientific Ethical Committees for Southern Denmark (S-20130175) and Danish Data Protection Agency (14/8158). Written informed consent was obtained from all patients before the procedure.
2.2
Invasive coronary angiography and NIRS/IVUS imaging of the culprit lesion
CAG was performed according to standard technique using the femoral approach. Culprit lesion was defined as a lesion ≥70% diameter stenosis visually assessed by the physician who performed the angiogram. If the patient had several significant stenoses and the culprit lesion was difficult to identify; right coronary artery (RCA), left anterior descending coronary artery (LAD) and left circumflex coronary artery (Cx) were chosen in the mentioned order.
To facilitate NIRS-IVUS catheter passage, a 2.0 mm balloon was inflated to minimize alteration of LCP while still achieving vessel patency. After administration of 100–200 μg intracoronary nitroglycerine, NIRS-IVUS catheter (TVC Imaging System, Infraredx, Burlington, MA) with IVUS frequency of 40 MHz was advanced over a BMW guide wire to a reference point of at least 5 mm distal to the culprit lesion. With an automated rotational pullback at a speed of 0.5 mm/s and 240 rpm the scanning was stopped when entering the guiding catheter or when a satisfying length of proximal reference segment was archived. Overall 3 pullbacks of each culprit lesion were acquired: after predilation, after stent implantation with nominal pressure at 11 atm for Synergy™ stent and lastly after post-dilation with a non-compliant balloon 0.5 mm larger than the chosen stent diameter. Immediately after pullback, data were displayed on the screen allowing the physician to precisely measure length of stenosis and choose an appropriate stent diameter using longitudinal and cross-sectional IVUS view together with a chemogram map. After the procedure the NIRS and IVUS images were recorded to a compact disk for quantitative analysis offline.
All of the lesions were treated with one single DES Synergy™ (Boston Scientific). The platinum chromium platform and a stent strut thickness of 74 μm increase the stent flexibility, but to avoid longitudinal stent deformation it has additional end connectors to increase the longitudinal robustness .
2.3
NIRS system
The near-infrared spectroscopy performs more than 30,000 chemical measurements per 100 mm of artery scanned through the blood, and each measurement interrogates 1–2 mm 2 of tissue at a depth of about 1 mm. The catheter can distinguish between different chemical compositions and identifies LCP based on different absorption pattern of each substance . The probability of LCP in the scanned vessel is then displayed in a chemogram, where x-axis is millimeters of pullback (0–120 mm), and y-axis is the catheter rotation (0°–360°) with red indicating a low probability and yellow indicating a probability >0.6 of LCP. Lipid-core burden index (LCBI) is a summary measure of the amount of LCP along the entire interrogated length of the vessel on a 0–1000 scale, while the maxLCBI 4mm is a segment with the maximum value of LCBI in a 4 mm segment. The block chemogram summarizes the chemogram in 2 mm length and 4 probabilities corresponding to the possibility (P) of LCP: red P < 0.57, orange 0.57 ≤ P ≤ 0.84, tan 0.84 ≤ P ≤ 0.98, yellow P > 0.98.
2.4
Offline analysis
Pre-intervention measurements of reference vessel diameter, minimum lumen diameter, degree stenosis and lesion length were accessed visually from CAG by the physician who performed the angiogram. Offline NIRS-IVUS analyses were performed using CAAS IntraVascular Software (Pie Medical Imaging, Maastricht, The Netherlands). All IVUS measurements were performed in accordance with the standards of American College of Cardiology and the European Society of Cardiology . Before performing the analyses reproducible landmarks such as side branches and calcium deposits were identified in each of the three pullbacks, resulting in exactly identical segments. The reference segments were 5 mm proximally and distally to the lesion (corresponding to the stented area). Overall analysis was lesion plus reference segments. At each 1 mm the cross-sectional area (CSA) of lumen, external elastic membrane (EEM) and plaque + media (EEM CSA − lumen CSA) were analyzed, and volumes were calculated using the Simpson’s rule by the software. The lesion (corresponding to the stent covered segment) was divided into three equal parts (proximal, mid and distal zone). A significant plaque shift in reference segments was identified as >1 mm 3 /mm increase in plaque volume index from predilation to post-dilation. Volume index defined as volume/lesion length (mean CSA) was also calculated due to the different lesion lengths. Stent malapposition was defined as ≥1 stent strut clearly separated from the intimal surface of the vessel wall with evidence of blood speckling behind the stent strut without overlapping a side branch. The remodeling index was defined as a ratio of (lesion/average reference) EEM area. Positive remodeling was defined as a remodeling index >1.05 and negative remodeling as a remodeling index <0.95.
From the NIRS acquisitions, the following measurements were performed: LCBI, maxLCBI 4mm , LCBI per length of the scanned artery (LCBI/L), the greatest angular extent of lipid-core plaque (0°–360°) from the cross-sectional view and length of LCP measured from block chemogram defined as yellow and/or tan blocks not interrupted by orange or red blocks. LCP compressed behind the stent is defined as LCBI ≥50 (lesion) after post-dilation. The study population divided into two groups: lesion with a large LCP (maxLCBI 4mm ≥ 500) and without (maxLCBI 4mm < 500).
2.5
Statistical analysis
Statistical analysis was performed using SPSS 22. Categorical variables were presented as counts and percentages, and group comparisons were made using chi-square test or Fisher’s exact test. Normally distributed continuous variables were displayed as mean ± SD, and compared using 2-tailed paired and unpaired t tests. If data were not normally distributed, Mann–Whitney U test or Wilcoxon signed-rank test was used instead. Correlations between variables were described with the use of Pearson correlation coefficient. P value <0.05 was considered statistically significant. The intra-observer variation evaluating the reproducibility of IVUS analyses was evaluated by re-measuring 10 lesions and calculating the percentage difference.
3
Results
3.1
Study population
Between March 2014 and August 2014, 25 patients with NSTEMI treated with PCI and stent implantation were enrolled in the present study. Culprit coronary arteries were following: RCA (n = 11), LAD (n = 8) and Cx (n = 6). Clinical characteristics of the study population (age 60.8 ± 10.1 years; 80% male) are presented in Table 1 ; values are shown for all patients and for those with maxLCBI 4mm ≥ 500 and maxLCBI 4mm < 500 with both groups well matched. Angiographic and procedural characteristics are presented in Table 2 .
| Total (n = 25) | maxLCBI 4mm < 500 (n = 13) | maxLCBI 4mm ≥ 500 (n = 12) | p Value | |
|---|---|---|---|---|
| Age, years, | 60.8 ± 10.1 | 61.8 ± 9.6 | 59.7 ± 11.0 | 0.62 |
| Male | 20 (80) | 10 (76.9) | 10 (83.3) | 1.00 |
| BMI, kg/m 2 | 28.6 ± 4.7 | 28.3 ± 4.9 | 28.9 ± 4.7 | 0.75 |
| Hypertension a | 17 (68) | 9 (69.2) | 8 (66.7) | 1.00 |
| Diabetes mellitus b | 2 (8) | 1 (7.7) | 1 (8.3) | 1.00 |
| Hyperlipidemia c | 19 (76) | 10 (76.9) | 9 (75) | 1.00 |
| Current smoker | 8 (32) | 4 (30.8) | 4 (33.3) | 1.00 |
| Ex-smoker | 13 (52) | 8 (61.5) | 5 (41.7) | 0.32 |
| Family history of CAD | 18 (72) | 9 (69.2) | 9 (75) | 1.00 |
| Peripheral vascular disease | 1 (4) | 1 (7.7) | 0 (0) | 1.00 |
| Prior myocardial infarction | 5 (20) | 1 (7.7) | 4 (33.3) | 0.16 |
| Prior PCI | 3 (12) | 1 (7.7) | 2 (16.7) | 0.59 |
| Prior CABG | 0 (0) | 0 (0) | 0 (0) | – |
| Prior stroke | 1 (4) | 1 (7.7) | 0 (0) | 1.00 |
| Multivessel disease | 12 (48) | 5 (38.5) | 7 (58.3) | 0.32 |
| Lipid lowering drugs d | 7 (28) | 2 (15.4) | 5 (41.7) | 0.20 |
| LVEF, % | 52.2 ± 9.1 | 52.3 ± 11.3 | 52.1 ± 6.6 | 0.47 |
| Normal ≥55% | 14 (56) | 8 (61.5) | 6 (50) | 0.56 |
| Mild LV dysfunction (45%–54%) | 9 (36) | 4 (30.8) | 5 (41.7) | 0.69 |
| Moderate LV dysfunction (30%–44) | 1 (4) | 0 | 1 (8.3) | 0.48 |
| Severe LV dysfunction (<30%) | 1 (4) | 1 (7.7) | 0 | 1.00 |
| Laboratory data | ||||
| Total cholesterol, mmol/L | 4.9 ± 1.2 | 5.0 ± 1.0 | 4.8 ± 1.4 | 0.61 |
| LDL, mmol/L | 3.0 ± 1.1 | 3.0 ± 0.9 | 3.1 ± 1.4 | 0.98 |
| HDL, mmol/L | 1.1 ± 0.3 | 1.2 ± 0.3 | 1.0 ± 0.2 | 0.07 |
| TG, mmol/L | 1.7 ± 0.8 | 1.9 ± 0.8 | 1.5 ± 0.7 | 0.18 |
| HbA1c, mmol/mol | 37.7 ± 6.2 | 35.8 ± 4.0 | 39.8 ± 7.5 | 0.14 |
| Glucose, mmol/L | 6.3 ± 0.9 | 6.0 ± 0.6 | 6.6 ± 1.1 | 0.14 |
| Creatinine, μmol/L | 82.2 ± 17.6 | 79.8 ± 18.7 | 84.4 ± 16.7 | 0.49 |
| Leucocytes, 10 9 /L | 8.3 ± 2.6 | 8.6 ± 2.9 | 8.0 ± 2.2 | 0.59 |
| C-reactive protein, mg/L | 16.8 ± 36.8 | 7.9 ± 16.1 | 26.4 ± 49.7 | 0.87 |
| Hemoglobin, mmol/L | 8.8 ± 0.8 | 8.8 ± 1.1 | 8.8 ± 0.6 | 0.93 |
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