Culprit lesion remodelling and long-term prognosis in patients with acute coronary syndrome: an intravascular ultrasound study

Aims Positive arterial remodelling is recognized as one of the morphological characteristics of the vulnerable plaque. Limited data are available on a long-term outcome of acute coronary syndrome (ACS) patients with culprit lesion positive arterial remodelling (PR). The aim of this study was to investigate the long-term impact of culprit lesion PR in patients with ACS. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Keywords dial infarction and 44 unstable angina pectoris) were successfully treated with IVUS-guided bare-metal stent implantation. The diagnosis of acute myocardial infarction was deﬁned as (i) continuous chest pain lasting . 30 min, (ii) ST-elevation . 2.0 mm in ≥ 2 contiguous precor-dial ECG leads, and (iii) an increase in serum creatine phosphokinase greater than three-fold the normal value. The diagnosis of unstable angina pectoris was deﬁned as (i) symptoms of ischaemia that were in-creasing or occurred at rest, with the last episode occurring no . 24 h before admission, and (ii) ischaemic changes as assessed by electrocar-diography (deﬁned as ST-segment depression or transient ST-segment elevation exceeding 0.05 mV, or T-wave inversion of 0.2 mV in two contiguous leads. Patient’s exclusion criteria include a prior history of angina pectoris, myocardial infarction, or bypass surgery. Lesion exclusion criteria include ostial lesions, severe target lesion calciﬁcation, bifurcation lesions, and restenotic lesions. Finally, 134 ACS patients (103 acute myocardial infarction and 31 unstable angina pectoris) with pre- and post-intervention IVUS imaging were selected and en-rolled in this study. There were 105 males and 29 females, a mean age of 64 + 10 years. as frequencies. Continuous variables were compared using unpaired- t tests. Binary variables were examined by the use of Fisher’s exact and x 2 tests. To identify predictors of clinical events, multivariable Cox proportional hazard models were used. Variables entered into were those probability of , 0.15. Cumulative event free-survival curves during the follow-up in with IR/NR were obtained by the Kaplan–Meier method with a log-rank test. To assess the impact of on very late ( . 1 year) clinical events, a landmark analysis was performed with a landmark set at 1 year. Statistical signiﬁ-cance was a value of P ≤ 0.05. All statistical analyses were performed with either the Statview version 5.0 (SAS Institute). A-20-year-old man was admitted to our outpatient clinic with a complaint of presyncope and cold hands. On physical examination, right arm blood pressure was higher than the left. Pulsations of the left brachial and radial artery were weak. Transthoracic echocardiography four-chamber view showed the descending aorta at the back of the left atrium ( Panel A and see Supplementary data online, Video S1A ). The transthoracic echocardiography suprasternal view demonstrated an enlarged artery in the proximal descending aorta ( Panel B and see Supplementary data online, Video S1B , as-terisk). Coronal ( Panel C ) and axial ( Panel


Introduction
Pathological observations 1 -3 and in vivo intravascular ultrasound (IVUS) studies 4 -6 have consistently demonstrated that positive arterial remodelling (PR) is one of the characteristics for the rupture prone or vulnerable plaque. Several IVUS studies have shown that arterial remodelling is related to a mid-term clinical outcome, mainly as a result of a higher incidence of restenosis and target lesion revascularization (TLR) after thrombolysis, 7 balloon angioplasty/directional atherectomy, 8 and bare-metal stent (BMS) implantation. 9 -11 It is, however, still unknown weather culprit lesion remodelling is related to a longer-term clinical outcome. More importantly, the impact of culprit lesion remodelling on mortality remains uncertain. Accordingly, we aimed to assess the long-term impact of preinterventional arterial remodelling on a long-term (.5 years) clinical outcome following IVUS-guided stent implantation in patients with ACS.

Study population
Study population and inclusion criteria were reported previously. 10 From January 2001 to June 2003, 179 ACS patients (135 acute myocar- † All the authors equally contributed with respect to data collections and manuscript preparation. dial infarction and 44 unstable angina pectoris) were successfully treated with IVUS-guided bare-metal stent implantation. The diagnosis of acute myocardial infarction was defined as (i) continuous chest pain lasting .30 min, (ii) ST-elevation .2.0 mm in ≥2 contiguous precordial ECG leads, and (iii) an increase in serum creatine phosphokinase greater than three-fold the normal value. The diagnosis of unstable angina pectoris was defined as (i) symptoms of ischaemia that were increasing or occurred at rest, with the last episode occurring no .24 h before admission, and (ii) ischaemic changes as assessed by electrocardiography (defined as ST-segment depression or transient ST-segment elevation exceeding 0.05 mV, or T-wave inversion of 0.2 mV in two contiguous leads. Patient's exclusion criteria include a prior history of angina pectoris, myocardial infarction, or bypass surgery. Lesion exclusion criteria include ostial lesions, severe target lesion calcification, bifurcation lesions, and restenotic lesions. Finally, 134 ACS patients (103 acute myocardial infarction and 31 unstable angina pectoris) with pre-and post-intervention IVUS imaging were selected and enrolled in this study. There were 105 males and 29 females, a mean age of 64 + 10 years.

Angiographic and IVUS procedure
Coronary angiography was performed following the standard femoral or radial approach. All patients received i.v. heparin (100 U/kg) before the procedures. After intracoronary nitroglycerin (200 mg) or isosorbide dinitrate (2 mg) administration, diagnostic angiography was performed. IVUS imaging was performed both before and after successful PCI. IVUS pullback imaging was performed at a rate of 0.5 mm/s using an automated pullback device. After baseline IVUS imaging, PCI was performed in a usual manner to achieve angiographical per cent diameter stenosis ,25% with the TIMI-3 flow. Following PCI, patients were maintained on a regimen of aspirin (81 -100 mg daily) plus ticlopidine (200 mg daily) for at least 4 weeks. In this study period, glycoprotein IIb/IIIa inhibitors were not available and thus not used during or after PCI. Similarly, clopidogrel was not available and thus was not used.

Intravascular ultrasound imaging protocol
A commercially available system (CVIS/Boston Scientific Corporation, San Jose, CA, USA) was used for IVUS examination. The system consisted of a single-element 40 MHz transducer mounted on the tip of a flexible shaft and rotating at 1800 rpm within a 2.6-French rapid exchange/common distal lumen imaging sheath. Ultrasound images were recorded on half-inch, high-resolution Super-VHS videotape for offline quantitative analysis.

Quantitative and qualitative coronary ultrasound analysis
All ultrasound images were reviewed and evaluated for both qualitative and quantitative parameters blinded to the clinical and angiographical information. The images were digitized to perform morphometric analysis with commercially available planimetry software (NetraIVUS TM , ScImage, Inc., CA, USA). Morphometric parameters consisted of external elastic membrane (EEM), lumen, and stent cross-sectional area (CSA). The EEM CSA was defined as the area within the media/adventitial border (that is, including lumen, plaque, and media). Plaque plus media (P + M) CSA was calculated as EEM CSA minus lumen or stent CSA. 12 Morphological parameters consisted of plaque type, the presence or the absence of thrombus, and plaque rupture. A plaque was divided into one of the following three types; fibrous, fibrofatty, or calcified. The fibrous plaque was defined as bright or brighter than the adventitia without shadowing. The fibrofatty plaque was defined as less bright than the adventitia. The calcified plaque was defined as brighter than the adventitia with acoustic shadowing. Intracoronary thrombus was defined as (i) distinct hypoechoic mass, brightly speckled plaque, channelling within the plaque, evacuated plaque cavity, or (ii) detached mobile mass. Plaque rupture was defined as the presence of a cavity that communicated with the lumen with an overlying residual fibrous cap fragment. 11 IVUS measurements were done at three cross-sections in the target segment: the tightest segment; the proximal and distal reference segments (defined as the location in the native vessel with the least amount of disease within 10 mm of the tightest segment and prior to the emergence of any major side branches).
A pattern of arterial remodelling was classified into the following two categories: (i) positive remodelling (PR) was defined as the ratio of the EEM CSA at the target lesion to that at the proximal reference of .1.05, and (ii) intermediate or negative remodelling (IR/NR) was defined as the ratio of the EEM CSA at the target lesion to that at the proximal reference of ≤1.05. 5,10,11 Clinical follow-up Clinical events were retrospectively confirmed by telephone contact (n ¼ 81) and/or a chart review (n ¼ 134). In this study, independent core laboratory to adjudicate clinical events was not used. Primary endpoint was major adverse cardiac event (MACE) defined as a composite of all-cause death, ACS, and TLR. TLR was defined as clinical (ischaemia)-driven repeat revascularization (either repeat PCI or CABG) of the initially treated target lesion including stented segments and peri-stent segments 5 mm from both proximal and distal stent edges. ACS was defined as ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, or unstable angina pectoris.
Secondary endpoints were (i) all-cause death and (ii) all-cause death and ACS.

Statistical analysis
Quantitative data were presented as a mean value + SD, and qualitative data were presented as frequencies. Continuous variables were compared using unpaired-t tests. Binary variables were examined by the use of Fisher's exact and x 2 tests. To identify predictors of clinical events, multivariable Cox proportional hazard models were used. Variables entered into the Cox proportional hazard models were those with a univariate probability value of P , 0.15. Cumulative event freesurvival curves during the follow-up in patients with PR vs. IR/NR were obtained by the Kaplan -Meier method with a log-rank test. To assess the impact of PR on very late (.1 year) clinical events, a landmark analysis was performed with a landmark set at 1 year. Statistical significance was a value of P ≤ 0.05. All statistical analyses were performed with either the Statview version 5.0 (SAS Institute).

Clinical characteristics
Baseline clinical characteristics, angiographical, and IVUS results were previously reported. 10 Pre-intervention PR was present in 83 (62%) lesions and IR/NR in 51 (38%) of 134 lesions. PR had a trend towards a higher incidence of diabetes (P ¼ 0.08) and significantly a lower incidence of smoking (P ¼ 0.002) ( Table 1).

Quantitative coronary angiography results
Baseline quantitative coronary angiography demonstrated no significant differences in angiographical indices between the two groups ( Table 1). In patients with acute myocardial infarction (n ¼ 103), PR was present in 68 lesions (66%) and IR/NR in 35 (34%) lesions. Pain-to-balloon time, pre-TIMI grade, final TIMI grade, and ejection fraction (n ¼ 69) were similar between the two groups ( Table 1).

Long-term clinical follow-up
Acute and mid-term (,2 years) clinical results were reported previously. Long-term clinical follow-up data are summarized in Table 3. An incidence of all-cause death showed a strong trend towards higher in patients with PR than that of the IR/NR (P ¼ 0.058). Similarly, an incidence of cardiac death tended to be higher in patients with PR (P ¼ 0.125). Stent thrombosis (definite/probable) was not documented in either group. Table 4 summarizes causes of death in 10 patients (one in the IR/NR group and nine in the PR group) who died during the follow-up. An incidence of ACS also showed a trend towards higher in patients with PR (P ¼ 0.176). Rates of TLR were significantly higher in patients with PR than IR/NR (P ¼ 0.01). All TLR procedures were performed within 12 months following the index procedure. In other word, all events observed after 12 months were either death or ACS. An incidence of MACE was significantly higher in patients with PR than IR/NR (44.6 vs. 19.6%, P ¼ 0.003).
By the Kaplan -Meier analysis, the MACE-free survival rate was significantly lower in patients with PR than in patients with IR/NR (log-rank, P ¼ 0.0037; Figure 1).
Landmark analysis demonstrated a trend towards a higher MACE rate in patients with PR than IR/NR ( Figure 2).
The survival rate was also significantly lower in patients with PR than in patients with IR/NR (P ¼ 0.043, Figure 3A). Similarly, The ACS-free survival rate was significantly lower in patients with PR than in patients with IR/NR (log-rank, P ¼ 0.039; Figure 3B). Table 4 summarizes causes of death in 10 patients who died during the follow-up. Congestive heart failure (n ¼ 3), sudden cardiac death (n ¼ 3), and cardiogenic shock (n ¼ 2) were main causes of death.
In a subset of patients with unstable angina pectoris as an initial clinical presentation (n ¼ 31), the MACE-free survival rate showed a trend towards lower in patients with PR than in patients with IR/ NR (log-rank, P ¼ 0.08). On the other hand, in a subset of patients  with acute myocardial infarction as an initial clinical presentation (n ¼ 103), the MACE-free survival rate was significantly lower in patients with PR than in patients with IR/NR (log-rank, P ¼ 0.02).

Discussion
The principal findings of this study were that culprit lesion PR was an independent predictor of a long-term clinical outcome including death, ACS, and TLR. In addition, patients with PR had significantly higher mortality and lower ACS-free survival, suggesting that the presence of culprit lesion PR is a possible marker for high risk or vulnerable patients. Our present results are quite concordant to the previous mid-term follow-up studies. 7 -11,13 Although previous studies showed a negative impact of the culprit lesion PR on the clinical outcome, it mainly resulted from a higher incidence of restenosis and, as a result, repeated revascularization. 8,9 Because of small sample size, short-follow-up period, and lower incidence of ACS and death during the mid-term follow-up, it has been unclear whether culprit lesion remodelling is related to these 'hard' endpoints. On the other hand, our long-term follow-up results suggest that culprit lesion PR was associated not only with repeated revascularization, but also death and ACS. A previous study using non-stent interventions (balloon angioplasty or atherectomy) showed that the incidence of repeated revascularization in lesions with PR was significantly higher, 8 possibly due to a lack of adaptive remodelling after angioplasty. 14 Similarly, another studies using BMS have suggested that the in-stent neointimal area was significantly larger in lesions with PR, resulting in an increased incidence of repeated revascularization. 9,15 It is reported that some patients with BMS implantation may develop ACS rather than stable angina pectoris as a clinical presentation of in-stent restenosis. 16 Therefore, it is possible that a higher incidence of restenosis may be related to poor prognosis. However, survival curves as well as ACS-free survival curves in our present study diverge over time even after 6-12 months. It is reported that    Remodelling and prognosis in ACS culprit lesion-related events are less frequently observed after 12 months. 17 Indeed, not a single TLR was performed after 12 months in our study. Therefore, a higher incidence of in-stent restenosis, which was exclusively performed within 12 months, alone does not explain excess mortality. It was initially believed that PR is an adaptive vascular response to accommodate for plaque accumulation. 18 Subsequently, in vivo IVUS studies have demonstrated the relationship between culprit lesion remodelling and clinical presentation, i.e. PR was more frequently found at the culprit lesions for ACS than those for stable angina. 4 -6 Because rupture of the vulnerable plaque is a major course of ACS, those vulnerable lesions with PR may have progressive thinning of the fibrous cap. 3 It is speculated that degradation and regeneration of extracellular matrix mediated by matrix metalloproteinases play a pivotal role in the remodelling process. 19 On the other hand, degradation of extracellular matrix from the fibrous cap by matrix metalloproteinases can lead to thinning of the fibrous cap. 20 A serial in vivo IVUS and optical coherence tomography observation demonstrated the relationship between arterial remodelling and thinning and disruption of the fibrous cap. 21 Lesions with expansive vessel remodelling during 6-month follow-up showed thinning of the fibrous cap. Conversely, lesions with constrictive vessel remodelling during the follow-up showed the thickening of the fibrous cap. Our previous observation of the same study population demonstrated that 57% of the non-culprit lesions requiring revascularization had PR. 10 Patients with PR at the culprit lesion may prone to develop PR in the non-culprit lesions and, as a result, recurrent ACS.
Previous studies suggested that culprit lesion plaque rupture may be associated with the clinical outcome in patients with ACS. 10,22 More recently, it is reported that plaque rupture of the peripheral circulation may be associated with vascular events. 23 Two-year follow-up data of our study population demonstrated that both PR and plaque rupture were independent predictors of cardiac events. 10 However, during the longer-term follow-up, the impact of plaque rupture disappeared. This is quite concordant to previous multicenter registry showing that culprit lesion remodelling rather than the presence or the absence of plaque rupture predicted a clinical outcome at 3 years in patients with ACS. 11 It is reported that patients with a ruptured plaque who were   Kaplan-Meier curves showed that the survival was significantly lower in patients with PR than in patients with IR/NR (log-rank, P ¼ 0.043). (B). The Kaplan-Meier curves demonstrated a significantly lower ACS-free survival rate in patients with PR than in patients with IR/NR (log-rank, P ¼ 0.039). treated using statins had favourable clinical results. 24,25 Therefore, plaque rupture may be a sequelae of the past events rather than active process. On the other hand, PR may represent an ongoing active process of plaque vulnerability. Previous analysis from lesions of our study population showed that PR was also frequently observed in non-culprit lesions of the ACS requiring intervention. 10 Therefore, it is possible that culprit lesion PR represents pan-vascular vulnerability of the entire coronary vessels.
Diabetes was another independent predictor of MACE in this study, concordant to numbers of previous studies. 26 -29 Diabetes is known as a predictor of in-stent restenosis after BMS 27 as well as Drug-eluting stent (DES). 28,29 More importantly, diabetes is strongly related to mortality in patients with ischaemic heart disease treated with DES. 30

Limitations
There are several limitations in this study. First, this is a singlecentre analysis with small numbers of patients. Therefore, this study is underpowered to detect differences in rare events such as mortality. Secondly, exclusions of the lesions without preintervention IVUS might have affected the results. Thirdly, RF signal analysis 31,32 was not performed. Therefore, the impact of specific plaque characteristics assessed by RF signal analysis on a clinical outcome is uncertain. Finally, because BMS was exclusively used in this study, the impact of pre-intervention remodelling on a long-term clinical outcome after DES implantation is uncertain. However, it is unlikely that the long-term survival can be modified by the use of DES, because a long-term safety profile of the currently available DES seems, at most, non-inferior to that of BMS. Previous IVUS studies suggested that impact of remodelling on neo-intimal proliferation may be different among different DES. 33 -35

Clinical implications
Our results suggest that patients with PR may have a poor longterm clinical outcome despite initially successful IVUS-guided BMS implantation. Aggressive risk reduction is especially warranted in ACS patients with diabetes and culprit lesion PR.
Conflict of interest: none declared.