Plaque Healing Research Articles

Comments regarding ‘Correlations Between Clinical Variables and Gene-expression Profiles in Carotid Plaque Instability’

A clever and effective idea from the Karolinska Institute in Stockholm, Sweden, with collaborations between a center of Molecular Medicine and the clinical divisions of Surgery and Internal Medicine, generated this paper, capitalising on an interesting project generating a “bio-bank” (BIKE) of gene expression profiles and clinical information from 106 patients undergoing carotid endarterectomy (CE). This paper may seem quite complex to grasp, especially for a vascular surgery readership, since it analyzes a large amount of data without any clear hypothesis testing. Therefore the reader needs to refer to the lengthy supplementary data, in order to understand the results. However, the effort of the authors’ in the microarray gene analysis on more than 100 CE specimens has to be applauded. Gene expression profiling is the measurement of the activity (the expression) of thousands of genes at once, to create a global picture of cellular and tissue functions. For this purpose, the authors utilized the DNA Microarray technology that measures the relative activity of previously identified target genes. Therefore, the authors “chose a biased approach and limited the genes studied to 317 candidates already thought to be associated with plaque instability or healing processes in the vessel wall, and correlated the gene expression analysis to clinical parameters”. The number of genes and the several clinical subgroups analyzed make statistical significant conclusions difficult to reach for any clinical translation.

Correlations Between Clinical Variables and Gene-expression Profiles in Carotid Plaque Instability

Objective Strokes, a major cause of disability, are often caused by embolism from unstable carotid plaques. The aim of this study was to validate a biobank of human carotid endarterectomies as a platform for further exploration of pathways for plaque instability. For this purpose, we investigated the relationship between clinical parameters of plaque instability and expression of genes previously shown to be associated with either plaque instability or healing processes in the vessel wall. Methods A database of clinical information and gene-expression microarray data from 106 carotid endarterectomies were used. Results Expression of matrix metalloproteinase (MMP)-9 and MMP-7 was 100-fold higher in plaques than in normal artery. In general, genes associated with inflammation (such as RANKL and CD68) were overexpressed in symptomatic compared with asymptomatic plaques. Plaques obtained from patients undergoing surgery within 2 weeks after an embolic event showed up-regulation of genes involved in healing reactions in the vessel wall (including elastin and collagen). Statin treatment, as well as echodense lesions, were associated with a more stable phenotype. Conclusion Here, we demonstrate that gene-expression profiles reflect clinical parameters. Our results suggest that microarray technology and clinical variables can be used for the future identification of central molecular pathways in plaque instability.

Frequency and Healing of Nonculprit Coronary Artery Plaque Disruptions in Patients With Acute Myocardial Infarction

The pathophysiology of plaque disruption and healing in nonculprit segments has not been clarified. Therefore, we investigated the frequency of plaque disruptions in nonculprit segments and whether those plaques are stabilized during follow-ups in patients with acute myocardial infarction (AMI) by serial angioscopic observations. Analyzed were 13 consecutive patients with AMI in whom infarct-related arteries were serially observed by angioscopy immediately after reperfusion and at 1- and 6-month follow-ups. Color of plaques was graded as 0 (white), 1 (slight yellow), 2 (yellow), or 3 (intensive yellow). Plaques with thrombus were defined as disrupted. Although number of nonculprit yellow plaques did not change from immediately after reperfusion to 6 months, the maximum color grade of those plaques and incidence of disrupted plaques in nonculprit segments (immediate vs 1 month vs 6 months 31% vs 8% vs 0%) decreased significantly by 6 months. Plaque stabilization as shown by disappearance of thrombus was significantly associated with plaque regression as shown by a decrease of maximum yellow color grade in nonculprit segments. In conclusion, patients with AMI frequently had disrupted and actively thrombogenic yellow plaques in nonculprit segments of the culprit vessel, and those plaques healed with decreases of yellow color grade and thrombogenicity during 6-months follow-up. Plaque disruption and healing occur not only at the culprit lesion but may be a pan-coronary process in patients with AMI.

The Role of Matrix Metalloproteinases in Atherothrombosis

The matrix metalloproteinase (MMP) family of enzymes is involved in arterial wall extracellular matrix degradation and remodeling. The latter activities have been implicated in a number of normal and pathologic processes, such as atherosclerotic lesion formation and progression, plaque destabilization and rupture, but also in plaque stabilization and healing. As a result, the MMPs have been explored as both therapeutic targets and diagnostic tools for the treatment and diagnosis of atherosclerotic cardiovascular diseases. In this review, we summarize experimental findings, genetic associations, and the biomarker potential of MMPs in atherothrombosis. In addition, the regulation and expression of MMPs in atherosclerotic plaques is discussed, with an emphasis on the role of lipid-derived inflammatory mediators as modulators of MMP activity.

Characterization of healing following atherosclerotic carotid plaque rupture in acutely symptomatic patients: an exploratory study using in vivo cardiovascular magnetic resonance.

BackgroundCarotid plaque rupture, characterized by ruptured fibrous cap (FC), is associated with subsequent cerebrovascular events. However, ruptured FC may heal following stroke and convey decreased risk of future events. This study aims to characterize the healing process of ruptured FC by assessing the lumen conditions, quantified by the lumen curvature and roughness, using in vivo carotid cardiovascular magnetic resonance (CMR).MethodsPatients suffering from transient ischemic attack underwent high resolution carotid MR imaging within 72 hours of the acute cerebrovascular ischemic event. CMR imaging was repeated at 3 and 12 months in 26 patients, in whom FC rupture/erosion was observed on baseline images and subsequent cerebrovascular events were recorded during the follow-up period. Lumen curvature and roughness were quantified from carotid CMR images and changes in these values were monitored on follow-up imaging.ResultsHealing of ruptured plaque was observed in patients (23 out of 26) without any ischemic symptom recurrence as shown by the lumen surface becoming smoother during the follow-up period, characterized by decreasing maximum lumen curvature (p < 0.05), increasing minimum lumen curvature (p < 0.05) and decreasing lumen roughness (p < 0.05) during the one year follow-up period.ConclusionsCarotid plaque healing can be assessed by quantification of the lumen curvature and roughness and the incidence of recurrent cerebrovascular events may be high in plaques that do not heal with time. The assessment of plaque healing may facilitate risk stratification of recent stroke patients on the basis of CMR results.

Smooth Muscle Cells Healing Atherosclerotic Plaque Disruptions Are of Local, Not Blood, Origin in Apolipoprotein E Knockout Mice

Signs of preceding episodes of plaque rupture and smooth muscle cell (SMC)-mediated healing are common in atherosclerotic plaques, but the source of the healing SMCs is unknown. Recent studies suggest that activated platelets adhering to sites of injury recruit neointimal SMCs from circulating bone marrow-derived progenitor cells. Here, we analyzed the contribution of this mechanism to plaque healing after spontaneous and mechanical plaque disruption in apolipoprotein E knockout (apoE-/-) mice. To determine the origin of SMCs after spontaneous plaque disruption, irradiated 18-month-old apoE-/- mice were reconstituted with bone marrow cells from enhanced green fluorescent protein (eGFP) transgenic apoE-/- mice and examined when they died up to 9 months later. Plaque hemorrhage, indicating previous plaque disruption, was widely present, but no bone marrow-derived eGFP+ SMCs were detected. To examine the origin of healing SMCs in a model that recapitulates more features of human plaque rupture and healing, we developed a mechanical technique that produced consistent plaque disruption, superimposed thrombosis, and SMC-mediated plaque healing in apoE-/- mice. Mechanical plaque disruption was produced in irradiated apoE-/- mice reconstituted with eGFP+ apoE-/- bone marrow cells and in carotid bifurcations cross-grafted between apoE-/- and eGFP+ apoE-/- mice. Apart from few non-graft-derived SMCs near the anastomosis site in 1 transplanted carotid bifurcation, no SMCs originating from outside the local arterial segment were detected in healed plaques. Healing SMCs after atherosclerotic plaque disruption are derived entirely from the local arterial wall and not circulating progenitor cells in apoE-/- mice.

Myocardial infarction: contemporary management strategies

Myocardial infarction (MI) is a common clinical diagnosis, associated with significant morbidity and mortality, not only in the short term, but also years following the index event. A more complete understanding of the pathophysiology of MI has ushered the era of multipronged treatment approach, with a combination of goal-directed revascularization, a broad adjunctive pharmacological therapy and aggressive secondary prevention measures. The goals of this article are to review the basic pathophysiological processes, which lead up to a clinical diagnosis of MI, to highlight the essential elements of clinical presentation and to summarize the evidence for comprehensive therapy. Emphasis has been placed on the choice of primary reperfusion therapy for ST-elevation MI, on risk-stratification of patients with non-ST elevation MI, and on rationale behind the selection of anti-ischaemic and antithrombotic therapy. Finally, evidence-based approach to secondary prevention is outlined.

Osteoprotegerin is not associated with angiographic coronary calcification

Coronary artery calcification may play a significant role in the pathophysiology of plaque progression and healing. We hypothesized that osteoprotegerin, an inhibitor of osteoclastogenesis, may participate in the calcification of coronary plaques or the response to injury after coronary stenting. A prospective registry was performed in 2004. Blood samples from 100 patients undergoing percutaneous coronary intervention (PCI) were obtained before PCI and 24 h after PCI. The concentrations of osteoprotegerin (OPG), C-reactive protein, interleukin-6, and soluble CD40 ligand (sCD40L) were determined by ELISA. Quantitative coronary angiography was performed to define the presence of culprit lesion calcification (CLC). Comparisons among markers of inflammation and tertiles of OPG were stratified with respect to CLC. Patients with CLC (n = 28) compared with no CLC (n = 71) were older (P < 0.01), had lower creatinine clearance (P < 0.01), lower hemoglobin (P = 0.02), and were less likely to smoke (P = 0.04). Patients without CLC were over twice as likely to present with a marker-positive acute coronary syndrome. CLC was associated with less pre-PCI platelet-mediated inflammation as measured by sCD40L (4.65 vs. 7.15 pg/ml, P = 0.05), but not with lower levels of OPG. Inflammatory cytokines increased significantly after PCI for patients with and without CLC. For patients in the highest tertile of OPG at baseline, there was a reduction in OPG after PCI. Systemic osteoprotegerin levels are not associated with angiographic calcification of culprit plaques. For patients with elevated levels of OPG prior to PCI, there is a significant reduction after PCI consistent with a counterregulatory role for OPG. Both calcified and non-calcified culprit plaques exhibited a similar inflammatory response to stent-mediated injury. After PCI, osteoprotegerin decreased while proinflammatory cytokines increased, which may be consistent with a counterregulatory role for osteoprotegerin.

Mo-PL1:3 Wounding and healing of vulnerable plaques — A two-edged sword of plaque inflammation

Mo-PL1:3 Wounding and healing of vulnerable plaques — A two-edged sword of plaque inflammation

Increased intimal apoptosis in coronary atherosclerotic vessel segments lacking compensatory enlargement

OBJECTIVESIn a histopathologic study, we assessed the balance of cell proliferation and apoptosis by counting the number of apoptotic and proliferating cell nuclear antigen-positive cells in freshly harvested atherectomy specimens from 34 patients.BACKGROUNDRemodeling of human coronary arteries is an adaptive process that alters vascular lumen size.METHODSIntravascular ultrasound was performed prior to atherectomy. Total vessel area (area within the external elastic lamina [EEL]), lumen area and plaque area were measured at the region of interest (ROI), and at a proximal and distal reference segment, utilizing the formula Δ(%)=100×(ROI−reference segment)/reference segment. Positive arterial remodeling (R+) resulting in luminal expansion was defined as ΔEEL >10%. Absence of remodeling (0 < ΔEEL <10%) and constrictive arterial remodeling (ΔEEL <0) were considered as neutral remodeling (R0) and negative remodeling (R−), respectively.RESULTSIn R− lesions, apoptotic indices (APO) were significantly elevated (17.17 ± 2.19%) compared with R+ lesions (4.89 ± 1.7%; p = 0.0007). In a rabbit iliac percutaneous transluminal coronary angioplasty model intimal apoptosis was increased four weeks after balloon angioplasty injury (APO 8.8 ± 0.03%) compared with contralateral untreated segments (APO 3.0 ± 0.04%, n = 6). Lesions with an EEL/intimal area <3.0 showed significantly more intimal apoptosis than untreated lesions (p = 0.02).CONCLUSIONSThe data indicate that constrictive remodeling of atherosclerotic coronary lesions is associated with increased apoptosis of intimal cells. We speculate that increased apoptosis is due to extensive plaque healing after episodes of symptomatic or asymptomatic plaque rupture.

Treatment of ischaemic heart disease. Role of drugs, surgery and angioplasty in unstable angina patients.

The term unstable angina should only be used to describe patients whose immediate prognosis is uncertain and the nature of the unstable disease may vary on a patient to patient basis, making broad categorization of such patients inappropriate. Unstable angina may be caused by extracardiac factors, such as uncontrolled hypertension and tachycardia, disruption of an atheromatous plaque, dynamic or intermittent coronary artery thrombosis, haemorrhagic dissection into an atheromatous plaque, epicardial coronary spasm or progression of atherosclerosis as a result of plaque healing. Control of symptoms using medical therapy with a combination of nitrates, beta-blockers and calcium antagonists is usually quite successful. In the absence of contra-indications, intravenous heparin, and possibly anti-platelet agents, should also be used in the acute phase of treatment. In addition, one aspirin a day is indicated unless there are definite contra-indications. If symptoms are relieved, evaluation and management should proceed as with chronic stable angina. Identification of patients with a poor prognosis should be the main indication for urgent revascularization. One of the best predictors of a poor prognosis in unstable disease is persistent pain despite optimum therapy. Urgent surgery should be considered in any patient with multivessel coronary artery stenosis who has evidence of persistent myocardial ischaemia, despite adequate medical therapy.

New insight into plaque healing after plaque rupture with subsequent thrombus formation detected by intravascular ultrasound.

New insight into plaque healing after plaque rupture with subsequent thrombus formation detected by intravascular ultrasound.

Morphological changes after percutaneous transluminal coronary angioplasty of unstable plaques. Insights from serial angioscopic follow-up.

To describe the morphological changes occurring in the months following percutaneous transluminal coronary angioplasty (PTCA) of unstable plaques. Coronary angioscopy is a relatively new technique to assess plaque morphology. Previous angioscopic studies have shown that unstable coronary lesions are characterized by complex morphology, evidence of plaque rupture, and intraluminal thrombi. No serial angioscopic studies have investigated the effects of PTCA on plaque morphology at such lesions. We studied 15 patients who underwent successful PTCA for an unstable coronary syndrome (unstable angina: n = 5; recent myocardial infarction: n = 10). Angioscopy was performed immediately before PTCA in 14 patients, immediately after PTCA in 13 patients, and at follow-up (225 +/- 62 days after PTCA) in all patients. Pre-PTCA, plaque morphology was defined as complex in 18%, ulcerated in 27%; the vessel was totally occluded in 18% of cases. Plaque colour was yellow in 75% of patients. A thrombus was identified at the lesion site in 71% of patients. Immediately post-PTCA, small surface disruptions and dissections were observed in 62% of patients. Plaque colour was yellow in 85% of cases. Seventy-seven percent of patients had an angioscopically visible thrombus at the PTCA site. At follow-up, however, plaque shape was almost uniformly classified as smooth concentric (93%); plaque colour was white in 93%; no thrombus was observed. These results demonstrate the healing of unstable plaques in the months following PTCA. The angioscopic appearance at 6 months is that of a stable plaque (smooth concentric, white, without thrombus). Whether this stable angioscopic appearance predicts long-term clinical stability remains to be determined.

Removal of surgically induced fibrous arterial plaques by argon ion laser angiosurgery using a multifiber delivery system: An experimental study in the dog

Removal of intravascular atherosclerotic obstructions by laser irradiation has gained the attention of many investigators, but has proven to be considerably more difficult to accomplish than initially envisioned. We tested, in an animal model, an argon ion laser delivery system that permits control of (1) laser power, (2) exposure time, and (3) laser beam spot size. The study was conducted on surgically, induced focal fibrous plaques in the carotid arteries of nine dogs. Plaque removal, vessel patency, and healing were evaluated angiographically and by light and electron microscopy at intervals up to 60 days after treatment. Results showed that intravascular obstructions could be removed, healing occurred, and vessels remained patent for up to 60 days.

Warfarin-related purple toes syndrome and cholesterol microembolization: Hyman BT, Landas SK, Ashman RF, et al. Am J Med 1987;82:1233–1237

Four patients had purple discoloration of their toes after warfarin therapy. They were diagnosed as having the purple toes syndrome on the basis of the following clinical features: (1) purple discoloration of the toes 3 to 8 weeks after the start of warfarin, (2) complete blanching with moderate pressure, (3) fading of the color with elevation, (4) pain and tenderness of the toes, and (5) variation in the intensity of color with time. All patients had palpable pedal pulses at the time of diagnosis and all had painful, asymmetric cyanotic discoloration of the toes of both feet. The diagnosis of cholesterol microembolization was confirmed by skin biopsy in three patients and by necropsy in a fourth. The authors refer to 14 additional cases from the literature in which cholesterol microembolization was preceded by warfarin therapy. In this regard, the purple toes syndrome may be similar to the blue toes syndrome in which microembolization from arterial aneurysms or ulcerated atherosclerotic plaques causes digital artery occlusion and ischemia, except that the blue toes syndrome has not been associated with anticoagulation. The authors speculate that warfarin may interfere with the healing of atherosclerotic plaques, thereby permitting dislodgment of microemboli. Cholesterol microembolization is reported to be a not uncommon, usually asymptomatic phenomenon in patients with atherosclerotic peripheral vascular disease. Many of these patients are also given warfarin for anticoagulation. Therefore it would be of clinical importance to know whether warfarin in some way increases the risk of embolization. Unfortunately, the histologic finding of microemboli in the four patients in this study who had previously taken warfarin does not prove a cause-effect relationship. Certainly, on the basis of this experience, anticoagulation should not be withheld from patients who have peripheral vascular disease with appropriate indications. However, perhaps this report will serve as a stimulus for a prospective study to verify the existence of this potentially important complication of warfarin.