Contemporary use of embolic protection devices in saphenous vein graft interventions: Insights from the stenting of saphenous vein grafts trial.

BACKGROUND: We sought to evaluate the contemporary use of embolic protection devices (EPDs) in saphenous vein graft (SVG) interventions. METHODS: We examined EPD use in the stenting of saphenous vein grafts (SOS) trial, in which 80 patients with 112 lesions in 88 SVGs were randomized to a bare metal stent (39 patients, 43 grafts, and 55 lesions) or paclitaxel-eluting stent (41 patients, 45 grafts, and 57 lesions). RESULTS: An EPD was used in 60 of 112 lesions (54%). A Filterwire (Boston Scientific) was used in 70% of EPD-treated lesions, Spider (ev3, Plymouth, Minnesota) in 12%, Proxis (St. Jude, Minneapolis, Minnesota) in 12%, and Guardwire (Medtronic, Santa Rosa, California) in 7%. Of the remaining 52 lesions, an EPD was not utilized in 13 lesions (25%) because the lesion was near the distal anastomosis, in 14 lesions (27%) because of an ostial location, in one lesion (2%) because of small SVG size, in two in-stent restenosis lesions (4%) because of low distal embolization risk, and in 22 lesions (42%) because of operator's preference even though use of an EPD was feasible. Procedural success was achieved in 77 patients (96%); in one patient a Filterwire was entrapped requiring emergency coronary bypass graft surgery and two patients had acute stent thrombosis. CONCLUSION: In spite of their proven efficacy, EPDs were utilized in approximately half of SVG interventions in the SOS trial. Availability of a proximal protection device could allow protection of approximately 25% of unprotected lesions, yet operator discretion appears to be the major determinant of EPD use.

Coronary-subclavian steal: presentation and management: two case reports.

Subclavian stenosis is a highly prevalent and underrecognized clinical entity. In patients with a history of coronary artery bypass grafting utilizing a left internal mammary artery, subclavian artery stenosis can cause coronary-subclavian steal, leading to myocardial ischemia. Traditionally, this has been treated surgically with a vascular bypass operation. Two cases of coronary-subclavian steal syndrome are presented, 1 treated percutaneously with angioplasty and stent, and 1 treated with a combined endovascular-surgical procedure.

Carotid artery stenting will replace carotid endarterectomy.

Stroke is the third leading cause of death in the United States. Carotid artery stenosis represents one of the most common etiologies of stroke. The current treatment modalities available for the treatment of carotid artery stenosis are carotid endarterectomy (CEA) and carotid artery stenting (CAS). Several clinical trials comparing CEA with medical management showed superiority of the surgical arm; however, the applicability of these results to the general population is limited by the fact that the patients and surgeons enrolled in these trials were carefully selected, and the optimal medical therapy used does not meet the current treatment standards. Carotid artery stenting has emerged as a treatment alternative to CEA, as shown in randomized trials comparing the 2 treatment modalities. Recent data from large-volume CAS registries indicate that percutaneous treatment of carotid artery stenosis compares favorably to CEA. Furthermore, the CAS trial designs make these results more applicable to the community standards. These data suggest that CAS will become the treatment of choice in patients with carotid artery stenosis.

Clinical safety of magnetic resonance imaging early after coronary artery stent placement.

OBJECTIVES: Our aim was to examine the rate of adverse cardiac events in patients undergoing magnetic resonance imaging (MRI) <8 weeks after coronary stent placement. BACKGROUND: The risk of coronary stent thrombosis from dislodgement due to MRI early after stent placement is not well defined. Manufacturers recommend postponing MRI studies until eight weeks after coronary stent placement. METHODS: We analyzed the Mayo Clinic Rochester Percutaneous Coronary Intervention Database and examined records of 111 patients who underwent MRI <8 weeks after coronary stent placement treated with aspirin and a thienopyridine. Occurrence of death, myocardial infarction (MI), and repeat revascularization within 30 days of MRI were recorded. RESULTS: Magnetic resonance imaging (1.5 tesla) was performed within a median of 18 days (range, 0 to 54 days) after coronary stent placement. Four noncardiac deaths occurred, and three patients had repeat revascularization procedures. Stent thrombosis did not occur (95% confidence interval, 0% to 3.3%). CONCLUSIONS: Magnetic resonance imaging <8 weeks after coronary stent placement appears to be safe, and the risk of cardiac death or MI due to stent thrombosis is low. Postponing MRI does not appear to be necessary.

Clinical outcome of patients undergoing non-cardiac surgery in the two months following coronary stenting.

OBJECTIVES: We sought to determine the frequency and timing of complications at our institution when surgery was performed within two months of coronary stent placement. BACKGROUND: The optimal delay following coronary stent placement prior to non-cardiac surgery is unknown. METHODS: We analyzed the Mayo Clinic Percutaneous Coronary Intervention and Surgical databases between 1990 and 2000 and identified 207 patients who underwent surgery in the two months following successful coronary stent placement. RESULTS: Eight patients (4.0%) died or suffered a myocardial infarction or stent thrombosis. All 8 patients were among the 168 patients (4.8%, 95% confidence interval [CI] 2.1 to 9.2) undergoing surgery six weeks after stent placement; the frequency of these events ranged from 3.8% to 7.1% per week during each of the six weeks. No events occurred in the 39 patients undergoing surgery seven to nine weeks after stent placement (0%, 95% CI 0.0 to 9.0). CONCLUSIONS: These data suggest that, whenever possible, non-cardiac surgery should be delayed six weeks after stent placement, by which time stents are generally endothelialized, and a course of antiplatelet therapy to prevent stent thrombosis has been completed.

Frequency and correlates of coronary stent thrombosis in the modern era: analysis of a single center registry.

OBJECTIVES: The study examined the frequency, correlates, and outcome of patients with stent thrombosis within 30 days of stent placement. BACKGROUND: Patients in trials evaluating stents or dual antiplatelet therapy to prevent coronary stent thrombosis have generally had narrow inclusion criteria; the extent to which stent thrombosis rates in such trials represent current practice, particularly with the availability of newer stents, is unclear. METHODS: We performed a retrospective analysis of the Mayo Clinic Percutaneous Coronary Intervention database and identified all patients who received at least one coronary stent and dual antiplatelet therapy (aspirin and ticlopidine or clopidogrel for two to four weeks). RESULTS: Four thousand five hundred nine patients underwent successful coronary stent implantation and were treated with dual antiplatelet therapy between July 1, 1994, and April 30, 2000. Stent thrombosis occurred in 23 patients (0.51%; 95% confidence interval 0.32%, 0.76%) within 30 days of stent placement. Multivariate analysis using bootstrap model selection to avoid over-fitting the model indicated that only the number of stents placed was an independent correlate of stent thrombosis (odds ratio 1.80, p < 0.001). The frequency of death and frequency of nonfatal myocardial infarction (MI) among the 23 patients with stent thrombosis were 48% and 39%, respectively. CONCLUSIONS: Stent thrombosis is even more rare in the current era than in earlier trials. Number of stents placed was an independent correlate of stent thrombosis. Most patients who suffer stent thrombosis either die or suffer MI.

Outcome of patients undergoing balloon angioplasty in the two months prior to noncardiac surgery.

We report on the incidence of adverse cardiac events in 350 patients who underwent noncardiac surgery within 2 months of successful balloon angioplasty (BA) at our institution between 1988 and 2001. Three patients died perioperatively (n = 1) or had myocardial infarction (n = 2) (0.9%, 95% confidence interval [CI] 0.2% to 2.5%), which is a lower incidence than that reported for patients undergoing noncardiac surgery after stenting (3.9% to 32%). One patient died, and 2 had a nonfatal myocardial infarction. All 3 (1.6%, 95% CI 0.3% to 4.6%) were among the 188 patients who underwent surgery within 2 weeks of BA. Repeat target vessel revascularization was performed in 10 patients (2.9%, 95% CI 1.4% to 5.2%): in 3 (1.6%, 95% CI 0.3% to 4.6%) of 188 patients who underwent surgery within 2 weeks of BA and in 7 (5.1%, 95% CI 2.1% to 10.2%) of 138 patients who underwent surgery within 3 to 7 weeks of BA. Therefore, in patients in whom percutaneous coronary revascularization is required before noncardiac surgery, BA appears to be safe, especially in patients who need to undergo surgery early after percutaneous coronary intervention.

Incidence, correlates, management, and clinical outcome of coronary perforation: analysis of 16,298 procedures.

BACKGROUND: Coronary perforation is a serious but uncommon complication of percutaneous coronary intervention (PCI) and is associated with significant morbidity and mortality. METHODS: We performed an analysis of the Mayo Clinic PCI database. Clinical records, procedural reports, and angiographic studies were reviewed. Multiple logistic regression analysis was performed to identify clinical, procedural, anatomic, and angiographic correlates of coronary perforation. RESULTS: A total of 16,298 PCI procedures were performed between January 1990 and December 2001. We identified 95 coronary perforations (0.58%; 95% CI, 0.47-0.71). The incidence of coronary perforation varied with time. Correlates of coronary perforation included the use of an atheroablative device and female sex. Twelve patients (12.6%) sustained an acute myocardial infarction, and cardiac tamponade developed in 11 patients (11.6%). Management strategies included reversal of heparin, pericardiocentesis, placement of a covered stent, and surgical repair. Seven patients died (7.4%). CONCLUSIONS: Coronary perforation during PCI is rare, but is associated with significant morbidity and mortality. The variable frequency of perforation may be explained by temporal variations in the use of atheroablative devices.

Safety and efficacy of aspirin, clopidogrel, and warfarin after coronary stent placement in patients with an indication for anticoagulation.

BACKGROUND: Dual antiplatelet therapy with aspirin and clopidogrel has replaced aspirin and systemic anticoagulation with warfarin as the preferred antithrombotic therapy after percutaneous coronary intervention (PCI) with stent placement. However, a number of patients have indications for all 3 drugs. We sought to determine the frequency and type of hemorrhagic complications in patients who undergo systemic anticoagulation with warfarin while receiving aspirin and clopidogrel after a PCI with stent placement. METHODS: We performed a retrospective analysis of the Mayo Clinic PCI database and identified 66 consecutive patients who were discharged from hospital after PCI between January 2000 and August 2002 (inclusive) receiving a combination of dual antiplatelet therapy (aspirin and clopidogrel) and systemic anticoagulation (warfarin) to determine the incidence of bleeding and other clinical events during the treatment period. RESULTS: Six patients (9.2%; 95% CI, 3.5-19.0) reported a bleeding event; 2 patients required a blood transfusion. No patient died or sustained a myocardial infarction or stent thrombosis. CONCLUSIONS: The risk of bleeding may be increased in patients treated with aspirin, a thienopyridine, and warfarin early after PCI with stent placement.

Routine intravascular ultrasound scanning guidance of coronary stenting is not associated with improved clinical outcomes.

PURPOSE: The purpose of the current study was to determine whether there is any incremental benefit to routine intravascular ultrasound (IVUS) guidance of percutaneous coronary intervention. METHODS AND RESULTS: We compared the outcome of 796 patients who underwent an IVUS study (IVUS group) during the index stent procedure with 8274 patients who did not have an IVUS study (angiography group). The primary end point was the composite end point of death, myocardial infarction, or ischemia-driven target vessel revascularization within 9 months of the index stent procedure. There were statistically significant differences in multiple procedural characteristics. Most importantly, those patients who underwent an IVUS study had a larger postprocedural minimal lumen diameter and smaller postprocedural percent diameter stenosis. However, there was no significant difference between the IVUS group and the angiography group with respect to the primary end point (RR 1.10, 95% CI 0.91, 1.32) or any of the individual clinical end points. Adjustment for multiple clinical and procedural characteristics did not significantly alter these findings. CONCLUSIONS: These data suggest that the routine performance of IVUS during stent placement influences the performance of the procedure, as judged by differences in procedural characteristics, but does not improve clinical outcome at 9 months.

Distal protection devices during percutaneous coronary and carotid interventions.

Distal embolization of particulate matter complicates percutaneous coronary and peripheral interventions more often than had been recognized until recently. A number of distal protection devices are under development. The PercuSurge GuardWiretrade mark is a balloon occlusion thrombectomy device approved by the United States Food and Drug Administration for saphenous vein graft intervention. A number of filter devices utilize an expandable filter mounted on the angioplasty guidewire to facilitate entrapment of particles and safe removal. The Parodi Anti-Emboli Systemtrade mark is an example of a catheter occlusion device that establishes protection by reversing blood flow in the target vessel.

Safety and efficacy of cutting balloon angioplasty: the Mayo Clinic experience.

UNLABELLED: A number of evolving clinical indications for cutting balloon angioplasty (CBA) have been described in the clinical literature, including angioplasty-resistant stenoses, in-stent restenosis, ostial lesions and small vessel disease. METHODS: We analyzed the Mayo Clinic PTCA registry and report procedural and in-hospital clinical outcomes in 100 patients (103 procedures, 114 lesions) undergoing CBA. RESULTS: CBA was successfully completed in 109 lesions (96%). The majority of lesions (73%) required additional treatment with either balloon angioplasty (39%) or stent implantation (34%). Severe intimal dissection resulting in at least 50% luminal obstruction occurred in 13 lesions (11%). A single incident of branch occlusion was documented, resulting in ST elevation myocardial infarction. There were no incidents of vessel perforation, urgent percutaneous or surgical target vessel revascularization, or in-hospital death. CONCLUSION: CBA is feasible and safe, with a low incidence of procedural complications and in-hospital adverse cardiac events when used primarily for in-stent restenosis.

Association of carotid artery intima-media thickness with complex aortic atherosclerosis in patients with recent stroke.

This study was undertaken to determine whether carotid intima-media thickness can predict complex aortic atherosclerosis. A retrospective review was conducted of 64 consecutive patients who underwent transesophageal echocardiography and carotid ultrasonography for evaluation of recent ischemic stroke at MCP Hahnemann University, Medical College of Pennsylvania Hospital between January 1, 1999, and December 31, 1999. The mean age was 65+/-14 years and 59% of the patients were women. Thirty-nine patients (61%) had carotid atherosclerosis (defined as an intima-media thickness > or =1 mm) and seven patients (11%) had complex aortic atherosclerosis (defined as the presence of protruding atheroma > or =4 mm thick, mobile atherosclerotic debris, or plaque ulceration in any aortic segment by transesophageal echocardiography). Compared to patients without complex aortic atherosclerosis, patients with complex aortic atherosclerosis were more likely to have hypercholesterolemia (19% vs 57%, p = 0.05) and a carotid intima-media thickness of 2 mm or greater (35% vs 86%, p = 0.02). A carotid intima-media thickness of 2 mm or more had 86% sensitivity, 65% specificity, 23% positive predictive value, 97% negative predictive value, 2.5 positive likelihood ratio, and 0.22 negative likelihood ratio for the diagnosis of complex aortic atherosclerosis. Carotid intimamedia thickness measurement can be used to noninvasively estimate the probability of complex aortic atherosclerosis. A carotid intima-media thickness less than 2 mm makes complex aortic atherosclerosis very unlikely.

Ventricular assist device support for management of sustained ventricular arrhythmias.

We describe herein the cases of 2 patients who had ventricular arrhythmias. In one, a short-term biventricular assist device, the ABIOMED BVS 5000, was placed because the patient had sustained ventricular tachycardia and could not be weaned from cardiopulmonary bypass. Excellent hemodynamic support was maintained for several days while the antiarrhythmic therapy was maximized. Sinus rhythm was restored, and the patient was successfully weaned from the ventricular assist device. However, the substrate for the arrhythmia persisted, and a recurrence, 1 week later, resulted in the patient's death. In the 2nd patient, the use of an implantable left ventricular assist device was successful in temporarily alleviating the ventricular tachycardia associated with ischemic cardiomyopathy. However, after 2 days of device assistance, the patient experienced a recurrence of the tachycardia, which degenerated into ventricular fibrillation with a marked deterioration in the patient's hemodynamics. The arrhythmia persisted despite multiple attempts at external cardioversion, and internal cardioversion and placement of an automatic implantable cardioverter-defibrillator were necessary. This treatment, along with repeated boluses of amiodarone, led to successful suppression of the arrhythmias, and the patient eventually underwent transplantation. The mechanical hemodynamic support of the circulation by ventricular assist devices was effective in supporting these 2 patients who had sustained ventricular arrhythmias.

Angiographic success and procedural complications in patients undergoing retrograde percutaneous coronary chronic total occlusion interventions: a weighted meta-analysis of 3,482 patients from 26 studies.

BACKGROUND: The efficacy and safety profile of retrograde chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has received limited study. We sought to perform a weighted meta-analysis of the success and complication rates of retrograde CTO PCI. METHODS: We conducted a meta-analysis of 26 studies published between 2006 and April 2013 reporting in-hospital outcomes of retrograde CTO PCI. Data on procedural success, frequency of death, emergent coronary artery bypass graft surgery (CABG), stroke, myocardial infarction (MI), perforation, tamponade, stent thrombosis, major vascular or bleeding events, contrast nephropathy, and radiation skin injury were collected. RESULTS: A total of 26 studies with 3482 patients and 3493 target CTO lesions were included. Primary retrograde CTO PCI was attempted in 52.4%. Pooled estimates of outcomes were as follows: procedural success 83.3% [95% confidence interval (CI): 79.0% to 87.7%]; death 0.7% (95% CI: 0.5% to 1.2%); urgent CABG 0.7% (95% CI: 0.4% to 1.2%); tamponade 1.4% (95% CI: 1.0% to 2.2%); collateral perforation 6.9% (95% CI: 4.6% to 10.4%); coronary perforation 4.3% (95% CI: 1.2% to 15.4%); donor vessel dissection 2% (95% CI: 0.9% to 4.5%); stroke 0.5% (95% CI: 0.2% to 1.0%); MI 3.1% (95% CI: 0.2% to 5.0%); Q wave MI 0.6% (95% CI: 0.4% to 1.1%); vascular access complications 2% (95% CI: 0.9% to 4.5%); contrast nephropathy 1.8% (95% CI: 0.8% to 3.7%); and wire fracture and equipment entrapment 1.2% (95% CI: 0.6% to 2.5%). CONCLUSIONS: Retrograde CTO PCI is associated with high procedural success rate and acceptable risk for procedural complications.

Prevalence and outcomes of intermediate saphenous vein graft lesions: findings from the stenting of saphenous vein grafts randomized-controlled trial.

BACKGROUND: We sought to examine the prevalence and progression rate of intermediate saphenous vein graft (SVG) lesions in the Stenting Of Saphenous vein grafts (SOS) trial. METHODS: The baseline and follow-up angiograms of 80 patients participating in the SOS trial were analyzed to determine the prevalence of intermediate (30-60% angiographic diameter stenosis) SVG lesions and their progression rate. RESULTS: At least one intermediate SVG lesion was present in 31 of 143 (22%) SVGs in 27 of 80 (34%) patients. Most intermediate lesions were present in the SOS stented SVGs (20 grafts in 19 patients). During a median follow-up of 35 months, angiographic follow-up was available for 28 grafts in 25 patients. Progression (defined as percent diameter stenosis ≥ 70% but <100% at follow-up angiography) was seen in 11 of 28 SVGs (39%) in 11 of 25 patients (44%). Progression rate at 12, 24 and 36 months was 28% and 47% and 84%, respectively. Seven of 11 patients (64%) with intermediate SVG lesion progression presented with an acute coronary syndrome and 8 (73%) underwent PCI. Four of the 28 grafts with intermediate lesions at baseline were 100% occluded at follow-up; all of those SVGs had received a stent in another location in the SVG as part of the SOS trial. CONCLUSIONS: Intermediate SVG lesions are common in patients undergoing SVG stenting, have high rates of progression and frequently present with an acute coronary syndrome. Further study of pharmacologic and mechanical treatments to prevent progression of these lesions is needed.

Recurrent cardiovascular events with paclitaxel-eluting versus bare-metal stents in saphenous vein graft lesions: insights from the SOS (Stenting of Saphenous Vein Grafts) trial.

UNLABELLED: The Stenting of Saphenous Vein Grafts (SOS) trial demonstrated a reduction in clinical and angiographic adverse events with paclitaxel-eluting stents (PES) compared to bare-metal stents (BMS) in saphenous vein graft (SVG) lesions, but the rate of recurrent adverse events has not been described. METHODS: We performed a post hoc, landmark analysis to evaluate the risk of event recurrence following a non-fatal initial event among the SOS trial patients (pts). RESULTS: During a median follow-up of 35 months, the 80 pts enrolled in SOS experienced a total of 78 major cardiovascular events (MACE): 51 in the BMS group and 27 in PES group. No MACE were found in 28 pts (35%) while 52 pts (65%) had at least one event. The initial event was death in 13 pts (16%). Among the 39 pts whose initial event was not fatal, 12 (31%) had one or more subsequent MACE (50% of which were definitely related to the study SVG). The mean and median number of MACE per patient was significantly higher in patients receiving BMS versus PES (1.3 ± 1.2 and 1 ± 1.26 versus 0.6 ± 0.7 and 1 ± 0.825, p = 0.005 and p = 0.008, respectively). The rate of a second MACE following an initial event was 17% in the PES group and 37% in the BMS group (p = 0.24). Ten of 12 pts with recurrent events had received a BMS (83%). CONCLUSION: Pts undergoing SVG stenting had a high rate of recurrent events after an initial non-fatal event. These events were often related to the target vessel and most occurred in pts who had received a BMS, further supporting the benefit of PES over BMS in SVG lesions.

Continued benefit from paclitaxel-eluting compared with bare-metal stent implantation in saphenous vein graft lesions during long-term follow-up of the SOS (Stenting of Saphenous Vein Grafts) trial.

OBJECTIVES: This study sought to report the long-term outcomes after drug-eluting stent (DES) implantation in saphenous vein graft (SVG) lesions in the SOS (Stenting of Saphenous Vein Grafts) trial. BACKGROUND: The long-term outcomes after DES implantation in SVGs are poorly studied. Apart from the SOS trial, the only other randomized trial comparing DES with bare-metal stents (BMS) in SVGs reported higher mortality in the DES group at 32 months. METHODS: In the SOS trial, 80 patients with 112 lesions in 88 SVGs were randomized to a BMS or paclitaxel-eluting stent (PES) and demonstrated improved short-term angiographic and clinical outcomes with PES. Extended clinical follow-up was subsequently obtained. RESULTS: Mean age was 67 ± 9 years, and all patients were men. The indications for stenting included acute coronary syndrome in 60% and stable angina in 31% of patients. The mean SVG age was 12 ± 6 years. The baseline characteristics of the patients in the 2 study groups were similar. Procedural success was achieved in 77 patients (96%). During a median follow-up of 35 months, compared with patients randomized to BMS, those receiving PES had a lower incidence of myocardial infarction (hazard ratio [HR]: 0.32, p = 0.01), target lesion revascularization (HR: 0.20, p = 0.004), target vessel revascularization (HR: 0.41, p = 0.03), and target vessel failure (HR: 0.34, p = 0.001) as well as a trend toward less definite or probable stent thrombosis (HR: 0.15, p = 0.08). All-cause mortality (HR: 2.04, p = 0.19) and cardiac mortality (HR: 0.62, p = 0.51) did not differ between groups. CONCLUSIONS: During long-term follow-up, use of PES was associated with significantly better clinical outcomes than BMS in SVG lesions. (Stenting of Saphenous Vein Grafts Trial [SOS]; NCT00247208).

Paclitaxel-eluting stents reduce neointimal hyperplasia compared to bare metal stents in saphenous vein grafts: intravascular ultrasonography analysis of the SOS (Stenting of Saphenous Vein Grafts) trial.

AIMS: To compare the intravascular ultrasonography (IVUS) findings between saphenous vein grafts (SVG) treated with paclitaxel-eluting stents (PES) vs. bare metal stents (BMS) in the Stenting Of Saphenous Vein Grafts (SOS) trial. METHODS AND RESULTS: Of the 80 SOS trial patients, 38 had both baseline and follow-up IVUS examination and were included in this substudy: 17 patients received 28 BMS in 26 lesions and 21 patients received 30 PES in 28 lesions. Quantitative IVUS analysis was performed to determine the volume of in-stent neointimal hyperplasia (NIH) - defined as the difference between stent volume and lumen volume in the stented segments. Baseline characteristics were similar between patients who did and did not undergo baseline and follow-up IVUS. Patients receiving BMS and PES had similar stent and lumen volumes immediately after stenting. At 12-month follow-up, compared to BMS, PES-treated lesions had significantly less NIH volume (3.4 vs. 21.9 mm³, p<0.001) and neointima hyperplasia progression (1.6 vs. 17.1 mm³, p<0.001). No significant differences were seen in the 5 mm segment proximal and distal to the stent. CONCLUSIONS: Compared to BMS, use of PES in SVG lesions is associated with significantly lower NIH formation, which may help explain the improved clinical outcomes with PES in these lesions.