Cornelius Borst

The relative importance of arterial remodeling compared with intimal hyperplasia in lumen renarrowing after balloon angioplasty. A study in the normal rabbit and the hypercholesterolemic Yucatan micropig.

BACKGROUND Although arterial renarrowing after angioplasty has been attributed largely to intimal hyperplasia, there has been no systematic effort to correlate the actual hyperplastic tissue mass with angiographic lumen reduction. Using balloon angioplasty in various animal restenosis models, we quantitatively assessed the separate contributions of intimal hyperplasia and arterial remodeling to angiographic late lumen loss. METHODS AND RESULTS Data used for this study were obtained from experiments of conventional and thermal (37 degrees C or 55 degrees to 90 degrees C) balloon angioplasty-treated femoral and iliac arteries in normal rabbits and conventional balloon angioplasty-treated iliac arteries in Yucatan micropigs fed either a normal or an atherogenic diet. Quantitative angiography was performed immediately before and after intervention and at 3 or 8 weeks thereafter, and late loss in lumen diameter was taken as the difference between arterial diameter immediately after treatment and at 3 or 8 weeks of follow-up. Intimal hyperplasia was quantified histologically as the area of tissue mass within the internal elastic lamina. We observed a consistent discrepancy between the actual late loss seen with angiography and the diameter reduction that could be explained by histological intimal thickness alone in both animal models. This discrepancy ranged from 86 +/- 3% of the late loss in the 8 weeks/37 degrees C group to 77 +/- 22% in the conventional group for rabbits and 52 +/- 23% in an atherogenic diet group (n = 10) to 89 +/- 11% in a normal diet group (n = 6) for pigs. This discrepancy appeared to be due predominantly to reduction of the area circumscribed by the internal elastic membrane, a process that is tentatively designated as arterial remodeling. In both the rabbit femoral artery and in the Yucatan iliac artery, remodeling, not intimal hyperplasia, correlated with angiographic late loss. CONCLUSIONS In both the normal rabbit and the normal and atherosclerotic pig, restenosis after angioplasty results from both intimal hyperplasia and arterial remodeling. The exact etiology of arterial renarrowing after angioplasty has important implications on the design of antirestenosis drugs and new coronary devices.

Relation of arterial geometry to luminal narrowing and histologic markers for plaque vulnerability: the remodeling paradox ☆

OBJECTIVE To relate local arterial geometry with markers that are thought to be related to plaque rupture. BACKGROUND Plaque rupture often occurs at sites with minor luminal stenosis and has retrospectively been characterized by colocalization of inflammatory cells. Recent studies have demonstrated that luminal narrowing is related with the mode of atherosclerotic arterial remodeling. METHODS We obtained 1,521 cross section slices at regular intervals from 50 atherosclerotic femoral arteries. Per artery, the slices with the largest and smallest lumen area, vessel area and plaque area were selected for staining on the presence of macrophages (CD68), T-lymphocytes (CD45RO), smooth muscle cells (alpha-actin) and collagen. RESULTS Inflammation of the cap or shoulder of the plaque was observed in 33% of all cross sections. Significantly more CD68 and CD45RO positive cells, more atheroma, less collagen and less alpha-actin positive staining was observed in cross sections with the largest plaque area and largest vessel area vs. cross sections with the smallest plaque area and smallest vessel area, respectively. No difference in the number of inflammatory cells was observed between cross sections with the largest and smallest lumen area. CONCLUSION Intraindividually, pathohistologic markers previously reported to be related to plaque vulnerability were associated with a larger plaque area and vessel area. In addition, inflammation of the cap and shoulder of the plaque was a common finding in the atherosclerotic femoral artery.

Arterial Remodeling: Mechanisms and Clinical Implications

The presentation of coronary atherosclerosis can be gradual, because of progressive flow-limiting stenosis and exertional angina, or dramatic, with plaque rupture and thrombosis causing unstable angina, myocardial infarction, or sudden death. The importance of arterial remodeling, or persistent change in vessel size, has recently become apparent in both situations. Arterial remodeling, not plaque size, has been identified as the primary determinant of lumen size in the presence of stable lesions. Similarly, luminal stenosis in transplant vasculopathy and with restenosis after angioplasty occur mainly because of inward remodeling rather than plaque growth. However, recent evidence also suggests that adequate outward remodeling may be associated with an increased risk of plaque rupture, the underlying cause of acute coronary syndromes and sudden cardiac death. The term “arterial remodeling” has previously been used to describe any change in vessel wall structure. More recently, however, it has been used specifically to refer to a change in vessel size (or cross-sectional area within the external elastic lamina), and it is on this entity that this review is focused. Inward remodeling denotes a reduction in vessel size. Outward remodeling denotes an increase in vessel size. Various other terms are used in the literature (the Table⇓). When outward remodeling is present but insufficient to prevent luminal stenosis, it is referred to as inadequate outward remodeling. View this table: Table 1. Terminology of Arterial Remodeling It has been known for more than a century1 that blood vessels enlarge to accommodate increasing flow to the organ downstream (eg, during natural growth or in left ventricular hypertrophy). Widespread interest in this phenomenon was stimulated by observations that radial enlargement of vessels (outward remodeling) can compensate for progressive growth of atherosclerotic plaques, thus postponing the development of flow-limiting stenosis.2 3 These pathological findings were subsequently supported by in vivo intravascular ultrasound (IVUS) studies that …

Atherosclerotic arterial remodeling and the localization of macrophages and matrix metalloproteases 1, 2 and 9 in the human coronary artery

Atherosclerotic luminal narrowing is determined by plaque mass and the mode of geometrical remodeling. Recently, we reported that the type of atherosclerotic remodeling is associated with the presence of histological markers for plaque vulnerability. Inflammation and matrix degrading proteases (MMPs) may play a role in both plaque vulnerability and in expansive arterial remodeling. The aim of the present study was to investigate the association between the remodeling mode and the localization of macrophages and MMPs in coronary atherosclerotic segments. From 36 atherosclerotic coronary arteries, 45 and 51 segments were selected with a vessel area that was >10% smaller and larger compared with the adjacent segments, respectively. No significant difference in staining for macrophages was observed between segments with expansive and constrictive remodeling. More MMP-2 and MMP-9 staining was observed in plaques of expansively remodeled segments compared with constrictively remodeled segments. In general, MMP-staining was less evident in the adventitial layer compared with the plaque. Zymography revealed more active MMP-2 in expansively remodeled segments compared with constrictively remodeled segments (340+/-319 vs. 199+/-181 (adjusted counts/mm(2)), respectively, P=0.019). Zymography did not show differences in inactive MMP-2 or MMP-9 among groups. It might be postulated that MMPs within the plaque play a causal role not only in plaque vulnerability but also in de novo atherosclerotic remodeling.

Paradoxical arterial wall shrinkage may contribute to luminal narrowing of human atherosclerotic femoral arteries

BACKGROUND This study was done to assess how local changes in vessel size, together with plaque load, determine luminal narrowing in atherosclerotic arteries. Fifty-one human femoral arteries were analyzed: 32 postmortem and 19 in vivo by 30-MHz intravascular ultrasound. METHODS AND RESULTS Histological and intravascular ultrasound cross sections were examined every 0.5 cm over an arterial segment 10 to 15 cm long. In each cross section we measured the lumen area and the area circumscribed by the internal elastic lamina (the IEL area). In each arterial segment, the cross section that contained the least amount of plaque was the reference site. For each cross section, the lumen area stenosis was expressed as percent of the lumen area in the reference site. Similarly, the IEL area was expressed as percent of the IEL area in the reference site (the relative IEL area). There was a significant negative correlation between the relative IEL area and the lumen area stenosis percentage (r = -.62, P < .001 for histology and r = -.66, P < .001 for intravascular ultrasound). When lumen area stenosis was less than about 25%, mainly compensatory enlargement was observed. When lumen area stenosis exceeded about 25%, however, mainly a decrease of the IEL area was observed, which is consistent with arterial wall shrinkage. Furthermore, the increase in plaque area does not account for the total loss of luminal area. There was a moderate correlation between an increase in plaque area and reduction of the corresponding lumen area (r = .49 and r = .56 for histology and intravascular ultrasound, respectively). CONCLUSIONS The decrease in luminal area cannot be attributed to plaque increase alone. Arterial wall shrinkage is a paradoxical mechanism that may contribute to severe luminal narrowing of the atherosclerotic human femoral artery.

In Vivo Evidence for a Role of Toll-Like Receptor 4 in the Development of Intimal Lesions

Background—Inflammation plays an important role in atherogenesis. The toll-like receptor 4 (TLR4) is the receptor for bacterial lipopolysaccharides and also recognizes cellular fibronectin and heat shock protein 60, endogenous peptides that are produced in response to tissue injury. To explore a possible role for this receptor in arterial obstructive disease, we determined the expression of TLR4 in the atherosclerotic arterial wall, including adventitia, and studied the effect of adventitial TLR4 activation on neointima formation in a mouse model. Methods and Results—Localization of TLR4 was studied in human atherosclerotic coronary arteries by immunohistochemistry and detected in plaque and adventitia. In the adventitia, not all TLR4-positive cells colocalized with macrophages. In primary human adventitial fibroblasts, expression of TLR4 was demonstrated by immunofluorescence, Western blot, and reverse transcriptase-polymerase chain reaction. Adding lipopolysaccharide to these fibroblasts induced activation of NF-&kgr;B and an increase of mRNAs of various cytokines. The effect of adventitial stimulation of TLR4 was studied in a mouse model. A peri-adventitial cuff was placed around the femoral artery. Application of lipopolysaccharide between cuff and artery augmented neointima formation induced by the cuff (intimal area±SEM, 9134±1714 versus 2353±1076 &mgr;m2, P <0.01). In TLR4-defective mice, application of cuff and lipopolysaccharide resulted in a smaller neointima than in wild-type mice (intimal area, 3859±904 &mgr;m2, P =0.02 versus wild type). Conclusions—A functional TLR4 is expressed in human adventitial fibroblasts and macrophages. Adventitial TLR4 activation augmented neointima formation in a mouse model. These results provide evidence for a link between the immune receptor TLR4 and intimal lesion formation.

Coronary artery bypass grafting without cardiopulmonary bypass using the octopus method: results in the first one hundred patients

OBJECTIVE Cardiopulmonary bypass and global cardiac arrest enable safe coronary artery bypass grafting but have adverse effects. In off-pump coronary bypass grafting, invasiveness is reduced, but anastomosis suturing is jeopardized by cardiac motion. Therefore the key to successful off-pump coronary bypass grafting is effective local cardiac wall stabilization. METHODS We prospectively assessed the safety and efficacy of the Octopus tissue stabilizer (Medtronic, Inc., Minneapolis, Minn.) in the first 100 patients selected for off-pump coronary bypass via full or limited surgical access. To immobilize and expose the coronary artery, two suction paddles (-400 mm Hg), fixed to the operating table-rail by an articulating arm, stabilized the anastomosis site. RESULTS One hundred forty-one grafts (96% arterial) were used to create 172 anastomoses (17% side-to-side), up to 4 per patient, on average 23 in the full access group (46 patients) and 1.2 in the limited access group (54 patients). Complications included conversion to cardiopulmonary bypass (2%), conversion from limited to full access (3%), myocardial infarction (4%), predischarge coronary reintervention (2%), and late coronary reintervention (1%). Median postoperative length of hospital stay was 4 days (limited access) or 5 days (full access). Rapid recovery allowed 96% of patients to resume social activities within 1 month. At the 6-month angiographic follow-up, 95% of anastomoses was patent. At the 2- to 22-month follow-up (mean, 13 months), 98 patients were in Canadian Cardiovascular Society class I and 2 patients were in class II. CONCLUSION These results suggest that off-pump coronary artery bypass grafting with the Octopus tissue stabilizer is safe. Early clinical outcome and patency rates warrant a randomized study comparing this methods with conventional coronary bypass grafting.

Techniques characterizing the coronary atherosclerotic plaque: influence on clinical decision making?

The composition of the atherosclerotic lesion rather than the degree of stenosis is currently considered to be the most important determinant for acute clinical events. Modalities capable of characterizing the atherosclerotic lesion may be helpful in understanding its natural history and detecting lesions with high risk for acute events. Speaking grossly, three histologic features of the vulnerable plaque have been reported: size of the atheroma, thickness of the fibrous cap, and inflammation. Imaging techniques are currently being deployed and are under development to aid visualization of the vulnerable coronary plaque. Most of these diagnostic modalities have the potential to detect locally one or more of the three histologically defined features of vulnerable plaque. This review will focus on imaging techniques that have been developed to characterize the atherosclerotic lesion. Most catheter-based visualization techniques will provide insight into components of the local atherosclerotic plaque which may limit their predictive value for the occurrence of a clinical event. Therefore, the clinical relevance of these imaging tools will be discussed.

Arterial remodeling in atherosclerosis, restenosis and after alteration of blood flow: potential mechanisms and clinical implications

Arterial remodeling is currently being recognized as an important determinant in vascular pathology in which narrowing of the lumen is the predominant feature. Not only expansive remodeling (enlargement), but also constrictive remodeling (shrinkage) is observed in de novo atherosclerosis, in restenosis and in transplant vasculopathy. Expansive remodeling prevents and constrictive remodeling enhances luminal narrowing by plaque formation or intimal hyperplasia. The mechanisms of the opposite remodeling modes is unknown. Insight into the processes that determine the direction of local arterial remodeling may help to develop new strategies to prevent arterial occlusive disease. In the present paper the current status of research in the field of arterial remodeling in cardiovascular disease is reviewed. Mechanisms of arterial remodeling, potential interventions to influence the mode of remodeling as well as the methodological limitations of remodeling studies are discussed.

Vertical Displacement of the Beating Heart by the Octopus Tissue Stabilizer: Influence on Coronary Flow

BACKGROUND In beating heart coronary artery bypass graft operations, biventricular pump failure, as observed after exposure of the posterior circumflex branches by sternotomy, may originate from mechanical obstruction to coronary flow. METHODS Regional coronary blood flow was measured in 8 anesthetized, paced, beta-blocked pigs, and the beating heart was fully retracted. RESULTS Displacement decreased cardiac output from 4.8 +/- 1.1 L/min (mean +/- standard deviation) to 2.8 +/- 1.2 L/min (p < 0.001), a 42% +/- 6% decrease that resulted in a decrease in mean arterial pressure by 48% +/- 6% (mean +/- standard error of the mean; p < 0.001) and a reduction in coronary blood flow in the left anterior descending coronary artery, the right coronary artery, and the circumflex coronary artery by 34% +/- 6%, 25% +/- 8%, and 50% +/- 10%, respectively (all p < 0.05 versus baseline). Relative circumflex coronary artery flow was 20.1% +/- 8.3% lower than the combined relative value of left anterior descending coronary artery and right coronary artery flows (p = 0.046). Subsequent 20 degrees head-down tilt significantly increased ventricular preload pressures and restored cardiac output and mean arterial pressure as well as coronary blood flow. CONCLUSIONS It is inferred that coronary blood flow was not mechanically obstructed during anterior displacement of the porcine beating heart, because augmentation of preloads by the maneuver of Trendelenburg restored coronary flow parallel to the recovery of cardiac output and mean arterial pressure while the heart remained retracted by 90 degrees.