Significance of intimal tears in the mechanism of luminal enlargement in percutaneous transluminal coronary angioplasty: correlation of histologic and angiographic findings in postmortem human hearts

Transluminal coronary angioplasty was performed in 17 coronary arteries with stenotic lesions of 15 postmortem human hearts. Morphologic changes of dilated vessels were examined angiographically and histologically. Angiographic evidence of coronary dissection was present in 8 (47%) of the 17 vessels. Histologic examination showed that intimal, medial, and adventitial tears were present in 17 (100%), 11 (65%), and one (6%) of the 17 vessels, respectively. In vessels with angiographic evidence of coronary dissection, the tear extended to more than one fourth of the circumference of the vessel. The tear was histologically demonstrated also in vessels which had no angiographic evidence of coronary dissection. Circumferential extension of the tear was greater in women than in men. There were no significant relationships between severity of the tear and histologic or angiographic characteristics of the target lesions. These results suggest that intimal or medial tears may frequently occur also in clinical cases treated with percutaneous transluminal coronary angioplasty and may be necessary for the success of the procedure.     

Intimal proliferation of smooth muscle cells as an explanation for recurrent coronary artery stenosis after percutaneous transluminal coronary angioplasty

The pathologic changes in the coronary arteries of three patients who died 5, 17 and 62 days, respectively, after percutaneous transluminal coronary angioplasty were studied. Changes in the vessel wall seen early after angioplasty included focal denudation of the endothelium, splits in the intima extending to and along the inner aspect of the media, focal intimal necrosis and adventitial hemorrhage. Extensive medial dissections were seen in the coronary arteries of the two patients who died 5 and 17 days after coronary angioplasty. Fibrin was deposited on the surface of the intima, within intimal cracks and in areas of intimal and medial necrosis. Focal proliferation of smooth muscle cells was prominent on neointimal surfaces of the coronary artery from the patient who died 17 days after angioplasty. The previously dilated coronary segment from the patient who died 62 days after angioplasty was stenosed by an extensive recent proliferation of smooth muscle cells that were distributed over the entire circumference of the intimal surface as well as within gaps in the old atherosclerotic plaques. This type of intimal proliferation would appear to be responsible for the recurrent coronary artery stenosis that develops in some patients after coronary angioplasty.     

Validation of an automated technique for determining the mechanical characteristics of coronary arteries during balloon angioplasty: laboratory assessment with necropsy segments

OBJECTIVES: To develop a technique for automatic inflation of a percutaneous transluminal coronary angioplasty (PTCA) balloon, with continuous measurement of the balloon pressure and volume; to validate the technique for determining the mechanical characteristics of coronary arteries. METHODS: During necropsy examination of the hearts of nine patients, 17 coronary artery samples were obtained for histological examination. A PTCA balloon was inserted into each artery, and the balloon pressure and volume were measured continuously during four repeat automatic inflations of the balloon. RESULTS: Of the 17 arteries, eight showed elastic, six plastic, and three fracture pressure-volume deformation characteristics. For the plastic deformations, the first inflation required a higher pressure than subsequent repeat inflations of 82 (61) kPa (mean (SD), range 25 to 175 kPa). For the three in the fracture group, the pressure drop because of the fracture occurred between 210 and 540 kPa. Two of these three showed a tear on visual inspection, and the other showed disruption of the intimal plaque on blinded histological examination. Of the six with plastic deformation characteristics alone, one showed a tear, and on histological examination two others showed splitting of the internal and external elastic lamina and one showed separation of intima and media. None in the elastic group showed any of these characteristics. CONCLUSIONS: Plastic and fracture deformation characteristics could be differentiated from elastic characteristics. Visual or histological evidence of fracturing was present in all three arteries identified during angioplasty as having pressure-volume fracture characteristics.     

Morphologic evidence of accelerated left main coronary artery stenosis: a late complication of percutaneous transluminal balloon angioplasty of the proximal left anterior descending coronary artery

Histologic evidence of restenosis after percutaneous transluminal coronary angioplasty has been confined to the site of previous dilation. In this study, attention is focused on the accelerated development of coronary stenosis proximal to the site of previous angioplasty in a necropsy patient who developed severe left main stenosis 4 months after successful dilation of the proximal left anterior descending coronary artery. The unique fibrocellular tissue proliferation at the site of previous angioplasty and involvement of the adjacent distal segment of the left main coronary artery make possible the histologic diagnosis of accelerated left main coronary artery narrowing. Mechanisms for development of coronary stenoses proximal to the angioplasty site include: intimal injury by guiding catheters, guide wires, dilating balloons or combinations; or retrograde extension of the fibrocellular response to an adjacent proximal coronary segment. Histologic analysis of left main coronary arteries from 11 patients who died within 72 hours of angioplasty of the left coronary system disclosed focal loss of luminal endothelium in 9. This finding suggests that intimal injury from catheters or balloons, or both, proximal to the angioplasty site probably initiates a fibrocellular reaction. The amount of underlying atherosclerotic plaque in the injured proximal coronary segment determines the clinical significance of a subsequent fibrocellular response.     

Coronary vessel stent implantation in patients with symptomatic dissections following balloon dilatation

Dissections after coronary balloon angioplasty are risk factors for acute or subacute vessel closure. Intracoronary stenting was developed to avoid this complication by wrapping the intimal and medial flaps against the vessel wall, which reduces the risk of acute thrombosis. A total of 17 stents were implanted into the coronary arteries of 10 patients with angiographically documented dissections after balloon angioplasty, who presented angina and ischemic ECG changes. Mean minimal stenosis diameter was 1.11 +/- 0.35 mm (65.1%) before, and 1.48 +/- 0.56 mm (53.9%, n.s.) and 2.45 +/- 0.62 mm (23.5%, p less than 0.005), respectively, after balloon angioplasty with and without taking the dissection membrane into account. All patients reported an immediate recovery of their anginal complaints after stent delivery, and ischemic ECG changes disappeared. The mean residual stenosis after coronary stenting was measured as 3.33 +/- 0.23 mm (0%, p less than 0.001). The immediate control angiograms and these after 24 h depicted smooth vessel walls without any irregulations at the site of implantation, and the mean residual stenosis diameter remained unchanged after 24 h (3.3 +/- 0.23 mm; 1.2%, p less than 0.001). No patient suffered acute myocardial infarction, one patient underwent coronary bypass surgery because of persisting episodes of angina pectoris. Thus, intracoronary stenting seems to be a secure and effective method to handle dissections after balloon angioplasty, and perhaps reduces the rate of acute complications and the need for emergency bypass surgery after coronary balloon angioplasty.     

Detection of coronary atherosclerosis in young adult hearts using intravascular ultrasound.

BACKGROUND. Coronary atherosclerosis has been demonstrated in young adults by postmortem pathology. Angiographic evaluation of coronary disease in young adults is limited by ethical issues and the insensitivity of angiography for detecting early pathology. Catheter-based intracoronary ultrasound has proven useful both in detecting and quantitating coronary disease, but the ultrasound appearance of young, angiographically normal, coronary arteries has not been well defined. METHODS AND RESULTS. Twenty-five subjects were examined with intracoronary ultrasound within 1 month of cardiac transplantation. Mean age of the donor hearts was 28 years (range, 14-43 years). Measurements of an index of intimal thickening were obtained at four left anterior descending coronary artery sites in each patient. All study patients had angiographically normal coronary arteries. Ultrasound in 14 subjects demonstrated a three-layered appearance of the coronary vessel wall with a mean intimal index of 0.16 +/- 0.07. The other 10 subjects, including all donors under the age of 25 years, had coronary vessel wall layers too thin to be imaged separately at the 30-MHz sound frequency. Five subjects had ultrasound evidence of focal intimal thickening greater than 500 microns. The donors of these hearts each had risk factors for coronary artery disease. Two subjects died within 5 weeks of their ultrasound study. Histological measurements of the vessel wall layers were similar to the corresponding ultrasound values. CONCLUSIONS. This study provides a reference for the intravascular ultrasound appearance of young adult coronary arteries and confirms pathology findings that young subjects with angiographically normal vessels have a range of coronary intimal thickening, which includes occasional evidence of focal, early atheromatous lesions.     

Distribution of intimal and medial thickening in the human right coronary artery: a study of 17 RCAs

OBJECTIVE: To quantify the distribution of intimal and medial thickening in human right coronary arteries (RCAs) obtained at autopsy. BACKGROUND: The shear and tensile stresses created by arterial bifurcation are believed to result in eccentric fibromuscular intimal thickening that leads to atherosclerosis. Vascular curvature has been cited as a cause of atherosclerosis; however, details of the location and extent of intimal and medial thickness in the largely curved human RCA are not adequately documented. METHODS: The right coronary arteries were obtained from 40 postmortem hearts and cut into 20-30 segments, each being 3-4 mm in length. Microscopic sections from the proximal, acute margin, and distal regions of the RCA were digitized around the circumference of the vessel. Seventeen arteries showed insignificant stenosis (<50%) and were selected for detailed examination. RESULTS: Seventy-one percent (12/17) of proximal sections displayed eccentric intimal thickening. Normalized ensemble averaging revealed a preferential thickening on the myocardial side of the artery. At the acute margin region where curvature is most pronounced and at the distal region, 51% (8/17) of the samples showed eccentric thickening, but the ensemble average thickening in these regions showed no preferential location. In these mildly diseased arteries, the thickened intima comprised of mainly smooth muscle cells with an extracellular matrix of collagen and some elastin. A relatively uniform medial smooth muscle layer was seen at all three locations. CONCLUSIONS: The proximal region of the RCA appears to be a site of intrinsic eccentric intimal thickening with maximum thickness on the myocardial side of the artery. Eccentric thickening does occur in the acute margin and distal regions; however, no distinct pattern or location was evident.     

Efficacy of peroxisome proliferative activated receptor (PPAR)-alpha ligands, fenofibrate, on intimal hyperplasia and constrictive remodeling after coronary angioplasty in porcine models

Constrictive remodeling and intimal hyperplasia play a prominent role in restenosis after angioplasty. It has been reported that the severity of constrictive remodeling and intimal hyperplasia correlate with adventitial angiogenesis and inflammation. Experimental evidence indicates that inflammation participates in angiogenesis, and therefore inhibition of inflammation may impair neovascularization. We tested whether fenofibrate, peroxisome proliferative activated receptors (PPAR)-alpha specific ligand, inhibits the early inflammation, adventitial angiogenesis, constrictive remodeling and intimal hyperplasia after angioplasty using porcine coronary arteries. Fenofibrate was tested in vivo, in 30 coronary arteries of 10 pigs (1g/day, orally) and was compared to placebo. Quantitative intravascular ultrasound and histopathologic assessment showed that fenofibrate increased lumen (6.28 mm(2) versus 5.15 mm(2)), vessel area (7.34 mm(2) versus 6.69 mm(2)) and inhibited constrictive remodeling. Inflammatory cell infiltration was evaluated with scanning electron microscopy 3 days after angioplasty and was significantly decreased in the treated vessels compared to control. Adventitial angiogenesis 3 days after angioplasty was significantly reduced in the injured vessels derived from the fenofibrate treated group compared to placebo. In conclusion, pharmacological activation of PPAR-alpha inhibited constrictive remodeling and neointimal hyperplasia after angioplasty through inhibition of inflammation and adventitial neovascularization.     

In vitro examination of the coronary artery wall after balloon angioplasty using intracoronary ultrasound

After autopsy 12 human coronary arteries were investigated by intracoronary ultrasound in order to measure the vessel wall dimensions and to detect damage on the vessel wall architecture after balloon angioplasty. Histology revealed artherosclerosis in 11/12 arteries. A total of 41 representative coronary segments were selected for further off-line ultrasound and histological analysis. Intracoronary ultrasound and histological measurements of the vessel wall thickness after balloon dilatation demonstrated a good correlation between the maximum thickness of the intima (histology 0.62 mm vs. intracoronary ultrasound 0.65 mm, r = 0.87) and the intima-media complex (0.80 mm vs. 0.83 mm, r = 0.87), in contrast to a weak one between the minimum thickness (r = 0.46 and r = 0.37). A total of 21 cases of damage occurred during angioplasty; intracoronary ultrasound detected 17. Further analysis showed that it imaged 10 of 11 cases of damage involving more than 30° of the vessel circumference and 7 of 10 cases of damage involving less than 30° of the vessel circumference. After balloon angioplasty of diseased coronary arteries, intracoronary ultrasound is therefore reliable in measuring the maximum wall thickness and in imaging damage involving more than 30° of the vessel wall circumference.     

Morphologic changes in the pulmonary arteries after percutaneous balloon angioplasty for pulmonary arterial stenosis

The pathologic appearance of pulmonary arteries subjected to balloon dilation was studied in four subjects with stenosis of pulmonary arteries. Nine vessels were dilated. Successful dilation in seven vessels was accompanied by intimal disruption and tearing of the media. In one vessel, at the site of a previous surgical procedure, dilation could not be accomplished. Histologically, this vessel was encased by reactive fibrous tissue, which may have precluded successful dilation. In one case, simultaneous rupture of the dilating balloon and the left pulmonary artery occurred. Morphologic examination could not adequately explain the cause of vessel rupture. Among the six vessels successfully dilated and studied 4 to 14 months after the dilation, the postdilation luminal diamter had been maintained. Tears in the intima and media as seen histologically had been filled in by scar tissue. In one artery a dilated segment distal to a residual obstruction revealed marked intimal proliferation.     

Main branch stenosis following aortic valve replacement

Three patients developed left main stem stenosis within some months after aortic valve replacement. In all of them diagnosis was confirmed by angiography and bypass surgery was performed successfully. Left main stem stenosis is a rare complication of aortic valve replacement and is due to cannulation and perfusion of the coronary arteries. The mechanism is probably injury of the vessel wall due to the perfusion-catheter, followed by intimal hyperplasia. A similar mechanism is assumed for restenosis after transluminal coronary angioplasty.     

Effectiveness of rotational atherectomy of right coronary artery ostial stenosis

Balloon angioplasty and stenting of right coronary ostial stenosis may frequently be impeded by lesion calcification, whereas rotational atherectomy, which ablates calcified plaque, should treat these lesions effectively. Accordingly, we evaluated procedural success and longterm clinical outcome of rotational atherectomy of right coronary ostial stenosis. Procedural data were obtained from a comprehensive interventional registry and follow-up information was obtained by chart review and patient enquiry. All patients who developed recurrent angina underwent angiographic restudy. During a 5-year interval, 119 patients underwent rotational atherectomy of right coronary ostial stenosis. Multilesion interventions were performed in 55% of patients. Ostial lesions were 3.73+/-3.69 mm in length (mean +/- SD), and 57.1% were significantly calcified. Reference vessel diameter was 3.42+/-0.56 mm. Maximum burr:artery ratio was 0.64+/-0.1 with adjunct balloon angioplasty in 89.1% and adjunct stenting in 9.2%. Procedural success (<50% residual stenosis without major complication) was 97.5%, with 1.7% uncomplicated failure and 0.8% Q-wave infarction. Maximum residual stenosis was 15+/-17%. During 6-month follow-up, available in 94% of patients, 82.7% remained angina-free, 10.9% developed recurrent angina due to right coronary ostial restenosis, and 6.4% developed recurrent angina due to another lesion. Two years after intervention, target lesion revascularization rate was 16%. Predictors of symptomatic angiographic restenosis were dissection >10 mm, final minimal luminal diameter <2.5 mm, lesion length >10 mm, restenotic lesion, and diabetes. We conclude that rotational atherectomy of right coronary ostial stenosis results in excellent acute procedural success and in low incidence of clinical recurrence, with a high proportion of patients remaining angina-free 2 years after intervention.     

Local Delivery of TGF-b Antibodies to Prevent Neointima Formation after Balloon Injury in a Pig Coronary Artery Model

BACKGROUND: The formation of neointima after vessel injury results from smooth muscle cell proliferation and extracellular matrix secretion. This process is activated by multiple growth factor release. Among these, Transforming Growth Factor-b (TGF-b) has been shown to play an important role. We hypothesized that local delivery of TGF-b antibodies could reduce neointima formation after balloon angioplasty. METHODS AND RESULTS: Using autoperfusion double-balloon catheters (Baxter, Irvine, California), we infused polyclonal TGF-b antibodies in 30 minutes, immediately after oversized balloon angioplasty in pig coronary arteries. Eleven coronary arteries received 100 m anti-TGF-b and thirteen served as controls. Animals were sacrificed 10 weeks later; coronary segments were harvested and processed for histologic quantitative assessment of the neointima. The extent of injury was similar in treated versus control vessels (39% +/- 5% vs. 30% +/- 4%) and there was no difference in intimal thickening (0.63 +/- 0.19 mm for treated vs. 0.52 +/- 0.12 mm for controls). A previously validated restenosis injury index (ratio of neointimal area to total wall area over extent of injury) was also similar in both groups, 1.46 +/- 0.15 for treated versus 1.55 +/- 0.14 for controls. CONCLUSION: Local delivery of a single dose of TGF-b antibodies failed to demonstrate a benefit on neointima formation in a pig coronary artery model.     

Transluminal coronary angioplasty of postmortem human hearts

Twelve autopsy human hearts were submitted to coronary angiography and coronary arterial balloon angioplasty. The effect of angioplasty was determined by follow-up coronary angiography as well as gross and microscopic inspection of the coronary arteries dilated. Fifty-four dilations were performed in 24 coronary arteries. Angiographically 50 of the 54 dilations resulted in a mean (± standard deviation) increase in luminal diameter ranging from 1.9 ± 0.9 to 2.7 ± 0.8 mm. Failure to increase luminal size was usually related to a predilation coronary diameter greater than that of the inflated angioplasty balloon.

Dilation resulted in mural disruption with intimai or medial tears, or both, in 65 percent of arteries dilated. Disruption was more frequent in arteries with atherosclerosis and calcification. The mechanism of luminal enlargement in coronary angioplasty may be focal damage to the arterial wall with intimai or medial splitting as opposed to plaque compression as initially suggested.     

Percutaneous coronary rotational angioplasty in humans: preliminary report

Percutaneous coronary rotational angioplasty was attempted in 12 patients. The procedure was performed with a flexible rotating shaft with an abrasive tip, varying in diameter from 1.25 to 3.5 mm, tracking along a central guide wire. Among the 12 patients (mean age 58 years), 4 had a stenosis in the left anterior descending coronary artery and 8 a stenosis in the right coronary artery. After the guide wire crossed the stenosis, the abrasive tip was slowly advanced and several passes across the stenosis were made. The residual stenosis was measured with computerized automatic quantitative coronary angiography. Success was defined as a reduction of percent stenosis by greater than 20%. If residual stenosis remained significant (greater than 50%), the procedure was completed by balloon dilation. The device could not be inserted in 2 of the 12 patients. Five of the 10 patients underwent rotational angioplasty alone, and 5 had the procedure completed by balloon dilation. The stenosis was significantly enlarged from 0.56 +/- 0.31 mm to 1.26 +/- 0.28 mm. The outline of the vessel appeared smooth and regular. There were no complications related to the procedure and all patients were free of symptoms when discharged 2 to 3 days after the procedure. Thus, coronary rotational angioplasty is a simple and safe procedure allowing marked dilation of the narrowed segment. However, long-term follow-up is required for further evaluation.     

Measurement of myocardial fractional flow reserve during coronary angioplasty in patients with old myocardial infarction

Although myocardial fractional flow reserve (FFRmyo) has been demonstrated to be a useful index for determining functional significance of coronary stenosis, the data in previous studies was derived from a highly selected group of patients. The aim of this study was to investigate the value of FFRmyo in a more clinically relevant group of patients, especially in patients who also had resistance vessel dysfunction. We measured FFRmyo in 20 consecutive patients who had undergone elective coronary angioplasty. FFRmyo was calculated by the ratio of Pc/Pa during intracoronary adenosine 5′-triphosphate (ATP; 50 μg in the left coronary and 20 μg in the right coronary artery) induced maximal hyperemia, where Pa represents mean aortic pressure obtained by the guiding catheter and Pc represents mean distal coronary pressure measured by a 2.1F infusion catheter. In total, 21 vessels were dilated and 14 of them were infarct-related arteries. The percent diameter stenosis significantly decreased from 80 ± 14% to 27 ± 17%, and the FFRmyo increased significantly from 0.46 ± 0.18 to 0.77 ± 0.15 after angioplasty. There was no significant differences in the FFRmyo between vessels with previous myocardial infarction and those without, after angioplasty (0.78 ± 0.18 vs. 0.76 ± 0.08). There was a significant correlation between the percent diameter stenosis and FFRmyo before (r = 0.83, P < 0.001) and after (r = 0.64, P < 0.01) angioplasty. In conclusion, FFRmyo significantly improved immediately after angioplasty in vessels with myocardial infarction as well as those without. These results led us to suggest the usefulness of FFRmyo in patients who had both epicardial stenosis and resistance vessel dysfunction. The significant correlation between FFRmyo and quantitative coronary arterial diameter stenosis would further support the more widespread use of FFRmyo in the clinical setting. Cathet. Cardiovasc. Diagn. 42:19–25, 1997. © 1997 Wiley-Liss, Inc.     

Ubiquitous atherosclerosis in coronary arteries without angiographically significant stenosis

Previous intravascular ultrasound (IVUS) studies have shown coronary artery atherosclerosis even in angiographically normal reference segment. However, IVUS has not been performed in all of the three major coronary arteries. A total of 50 patients with single-vessel disease underwent IVUS evaluation in the proximal two-thirds of the three major coronary arteries. Lumen and external elastic membrane cross-sectional areas were measured at 1-mm intervals. To compensate the difference in pullback length among coronary arteries, normalized total plaque and media volume (TPV) was calculated as TPV/number of slices in pullback × median number of slices in study population. Percent plaque and media volume (PPV) was calculated as TPV/Σ external elastic membrane cross-sectional area × 100. A cross section was defined as atherosclerotic if maximum intimal thickness exceeded 0.5 mm at any point in the vessel circumference. There was no significant difference in normalized TPV, PPV, and the incidence of abnormal intimal thickness between coronary arteries with and without significant stenosis. Frequency distribution of plaque burden was similar. Atherosclerosis is ubiquitous even in coronary arteries without angiographically significant stenosis. The extent of atherosclerosis is similar between coronary arteries with and without significant stenosis.     

Time course of smooth muscle cell proliferation in the intima and media of arteries following experimental angioplasty.

Smooth muscle cell (SMC) proliferation is known to be an important factor for the development of restenosis after percutaneous transluminal coronary angioplasty. To determine the time course of intimal and medial SMC proliferation and morphological changes after experimental angioplasty, an intimal atheroma was produced with repeated weak electrical stimulations in the right carotid artery of 45 male New Zealand White rabbits. Angioplasty was subsequently performed in 35 rabbits, and the proliferative responses were analyzed with histomorphological and immunohistological criteria at 3, 7, 14, 21, 28, and 42 days after intervention. A hemodynamic relevant stenosis after angioplasty was found in eight (23%) of 35 dilated arteries. In five rabbits the stenosis was due to a mural thrombus, and in three animals restenosis was caused by intimal SMC proliferation. In all dilated arteries the intimal wall thickness increased from 13 +/- 5 intimal cell layers (after electrical stimulation) to 33 +/- 14 cell layers during 28 days after angioplasty (p less than 0.05). Later than 4 weeks after angioplasty, no additional increase of intimal thickening occurred. Application of bromodeoxyuridine 18 and 12 hours before excision of the vessels allowed determination of the percent of cells undergoing DNA synthesis in the intima and media using monoclonal antibody against bromodeoxyuridine. SMCs were identified by alpha-actin staining. Immunohistological quantification of intimal SMC proliferation showed a maximum of cells undergoing DNA synthesis within the first 7 days after angioplasty (p less than 0.01). In contrast, medial proliferation of SMCs was delayed and showed a small but significant increase 21 days after dilatation (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Experimental technique of laser coronary endarterectomy and its immediate effects on atherosclerotic plaques in cadaver hearts

The immediate effects of carbon dioxide laser radiation were assessed in the normal canine aorta, the human atherosclerotic aorta, and 24 human coronary arteries from nine cadaver hearts. The parameters needed for precise control of laser energy were identified. Penetration of a 1-mm thick arterial wall required a minimum power (5 watts), power density (781 watts cm(2)), and radiant energy (1.5 joules). Use of an optimal pulse duration (30 msec or less) resulted in less thermal injury to the adjacent arterial wall. Laser radiation relieved stenosis and reopened totally occluded vessels in 21 of 24 coronary arteries. Coronary stenoses were not relieved in two heavily calcified arteries, and perforation occurred in another artery. In successfully treated arteries, laser coronary endarterectomy increased the luminal diameter from 25 to 100%.