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(Circulation. 1997;95:855-859.)
© 1997 American Heart Association, Inc.

Articles

Role of Compensatory Enlargement and Shrinkage in Transplant Coronary Artery Disease

Serial Intravascular Ultrasound Study

Tai Tian Lim, MD; David H. Liang, MD; Javier Botas, MD; John S. Schroeder, MD; Stephen N. Oesterle, MD; Alan C. Yeung, MD

the Division of Cardiovascular Medicine, Stanford (Calif) University School of Medicine.

Correspondence to Alan C. Yeung, MD, Division of Cardiovascular Medicine, Stanford University Medical Center, 300 Pasteur Dr, Stanford CA 94305.

	Abstract

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Background Compensatory enlargement of the vessel wall has been described in the early stages of native atherosclerosis. Whether compensatory enlargement plays a role in transplant coronary artery disease is not known. The objective of this study was to determine, by use of serial intravascular ultrasound (IVUS), whether compensatory dilation occurs in transplant coronary artery disease over time.

Methods and Results Seventy-five heart transplant recipients with 151 matched coronary segments were selected for the presence of intimal disease progression as detected by serial IVUS examinations 1 to 3 years apart. Intimal disease progression was defined as a >10% increase in intimal area (IA). IVUS catheter location in follow-up studies was verified angiographically in relation to branch vessels. Luminal area (LA) and total vessel area (TA) were measured at each site. Intimal area (IA=TA-LA) was calculated. Changes in IA (IA) and TA (TA) between baseline and follow-up IVUS were compared: IA, 2.9±0.2 mm²; TA, 2.7±0.4 mm². A remodeling index (RI) was defined as RI=TA/IA. Three subgroups could be distinguished: overcompensation (RI >1), partial compensation (RI 0 to 1), and no compensation or shrinkage (RI 0). Seventy-four segments (49%) showed overcompensation, 44 (29%) showed partial compensation, and 33 (22%) showed no compensation or shrinkage.

Conclusions In this study, serial IVUS shows that early after cardiac transplantation, a large proportion of the coronary segments with progression of intimal thickening have compensatory dilation of the vessel wall. However, a substantial number of coronary segments (22%) show no compensatory dilation or shrinkage. The progressive luminal narrowing in transplant patients may be due in part to vessel shrinkage or the lack of compensatory dilation over time.

Key Words: coronary disease • remodeling • transplantation • ultrasonics

	Introduction

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Transplant coronary artery disease is the leading cause of death in the cardiac transplant patient population after 1 year.^{1 2} The mechanism of this disease is thought to be immune in nature, with superimposition of such traditional cardiac risk factors as hyperlipidemia, hypertension, and diabetes. From multiple angiographic and IVUS studies, it is clear that the pathogenesis of this disease involves progressive intimal thickening. However, it is unclear whether arterial remodeling plays a significant role in the pathobiology of transplant coronary artery disease.^{3 4}

Compensatory enlargement of the vessel wall has been shown to occur in native coronary artery disease.^{5 6 7 8} These pathological and, more recently, IVUS studies have shown that the increase in plaque area is apparently uniformly accompanied by an increase in TA (estimated by internal elastic lamina area) until the degree of lesion area stenosis (IA/internal elastic lamina area) approaches 30% to 40%, beyond which compensatory enlargement may not occur and luminal narrowing becomes evident. Compensatory enlargement, however, does not always occur. Pasterkamp et al^{9 10} described shrinkage of total vessel area in human atherosclerotic femoral arteries and showed that this process may play a significant role in luminal narrowing.

The process of compensatory enlargement or shrinkage has not been studied in the pathogenesis of transplant coronary artery disease. Moreover, this population also offers a unique opportunity to observe this process over time, because previous studies have all used the spatial distribution of plaque as surrogate evidence of implied temporal progression of compensatory enlargement.

The objective of this study was to determine whether compensatory enlargement occurs with progressive intimal thickening in transplant coronary artery disease over time.

	Methods

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From 1991 to 1994, at least two IVUS studies were performed in 115 patients during their annual evaluations. Only studies that had nonbranching coronary segments accurately matched angiographically and ultrasonically in the two serial studies were considered further. Those coronary segments that had disease progression, defined as having at least a 10% increase in IA or an absolute increase of 1 mm² between the two IVUS studies, were selected. After the above criteria had been applied, 75 patients with 151 segments were qualified.

There were 62 men and 13 women. Their mean age was 46.6±0.6 years (range, 19 to 70 years) at the time of transplantation; mean time between transplantation and first IVUS study was 2.4±0.2 years (range, 0 to 13 years). The mean time between their first and second IVUS studies was 1.6±0.1 years (range, 1 to 3 years). The study protocol was approved by the Committee for the Protection of Human Subjects in Research at Stanford University Medical Center, and written informed consent was obtained from all subjects.

Ultrasound Imaging Procedure and Analysis
IVUS imaging was done with a 30-MHz ultrasound transducer and rotating mirror system enclosed within an acoustic housing at the tip of a 4.3F rapid-exchange catheter (Cardiovascular Imaging Systems Inc). The catheter characteristics have been reported previously in detail.¹¹ Sublingual nitroglycerin (0.4 mg) and intracoronary nitroglycerin (200 µg) were given before ultrasound imaging to prevent vasospasm and to allow reproducible measurement of vessel dimensions. After anticoagulation with heparin, the imaging catheter was introduced through an 8F guiding catheter over a 0.014-in coronary guidewire. The left main and proximal to middistal left anterior descending arteries were then imaged. Coronary segments <2 mm in diameter were not recorded. Besides continuous scanning of the artery, four distinct arterial sites per patient were determined for precise ultrasound measurements. Both intracoronary ultrasound and concomitant angiography of these sites were obtained.

The technique for replication of the imaging sites has been reviewed in detail in a recent article.¹² The projection that best showed the vessel to be studied, with the least foreshortening and vessel overlap, was chosen at the time of the original study. The height of the image intensifier and the C-arm angles were noted in the patient record so that this angulation could be duplicated in subsequent studies. A drawing and a video hard copy of this specific projection were obtained. The position of the radiopaque transducer in relation to the side branches visualized at the time of concomitant angiography was then filmed, marked in the drawing, and hard copied for future reference. Imaging of the same sites on subsequent examinations was done according to the notes, drawing, and photos obtained in the initial examination as well as a review of the cineangiogram. Each coronary site was again imaged simultaneously with ultrasound and contrast angiography on each follow-up study. Accuracy of matching of the imaging sites was then determined off-line for each site with side-by-side comparison of the follow-up and baseline angiograms. Ultrasonic imaging sites judged by consensus of two independent readers as not accurately matched visually within one guiding catheter diameter distance (2.6 mm) on the side-by-side images of the serial studies were excluded from analysis. As described by Liang et al¹³ from our institution, if adequate angiographic matching of sites was achieved, variability of IVUS measurements between two IVUS studies for vessel area, plaque area, and II were 9.5%, 7.9%, and 7.1%, respectively. Up to four sites were imaged in each patient.

IVUS Measurements
Ultrasound studies were recorded on S-VHS videotape and analyzed off-line. Gain settings were adjusted for optimal visualization of the vessel/lumen interface, and images were digitized. The frame with the largest lumen from the cardiac cycle immediately before angiography was selected for measurements. Measurements included the LA and, if intimal thickening was present, the TA, or area within the media layer. The IA was calculated by subtracting the luminal cross-sectional area from the total cross-sectional area (IA=TA-LA). The values were entered into a customized database that calculated an II (=IA/TA), a measure of plaque area. We have previously shown good reproducibility and low interobserver and intraobserver variability for the above-mentioned intravascular parameters.¹⁴

IA and TA between baseline and follow-up IVUS studies were compared, and the RI (=TA/IA) was calculated. The coronary segments were divided into the following categories: (1) RI 1, the TAIA, reflecting adequate compensation or overcompensation; (2) RI >0 and <1, TA<IA, reflecting partial compensation; and (3) RI 0, no increase in TA, representing no compensation or even a decrease in TA, reflecting "shrinkage" of the vessel.

Statistical Analysis
All data are expressed as mean±SEM for continuous variables and as percentages for discrete variables. Comparisons between groups were determined by Student's t test or ANOVA for differences in means. A two-sided value of P<.05 was considered statistically significant.

	Results

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One hundred fifty-one segments (34%) in 75 patients fulfilled the entrance criteria: (1) an increase in IA of >10% and (2) nonbranching segments accurately matched angiographically in the two serial studies. The mean increase of IA was 2.9±0.2 mm², and the mean increase in TA was 2.7±0.4 mm². Fig 1 is a plot of TA against IA (r=.3, P=.0003, TA=0.55IA+1.13). In 74 lesions (49%), the TA increased more than the IA (RI=5.6±1.4), ie, there was overcompensation. Partial compensation (RI=0.5±0.1) was seen in 44 lesions (29%), and no compensation or shrinkage (RI=-5.7±3.5) was seen in 33 lesions (22%). Of the 33 lesions, all had shrinkage of the vessel. These proportions were no different when the segments were stratified according to baseline II. Fig 2 illustrates examples of overcompensation and shrinkage.

View larger version (60K): [in this window] [in a new window]   Figure 1. Relation between increase in cross-sectional area of plaque and TA as measured by serial IVUS studies. In most segments, there is an increase in vessel size as plaque area increases. There is a subgroup (shaded) of patients in whom TA does not increase or may even decrease when the plaque area increases.

View larger version (86K): [in this window] [in a new window]   Figure 2. Examples of coronary segments with compensatory enlargement and shrinkage.

The mean II was also determined for each RI category. There was no significant difference in IIs at baseline between the three categories, with IIs of 0.14±0.02 (range, 0 to 0.43) for the overcompensation group, 0.17±0.02 (range, 0 to 0.52) for the partial compensation group, and 0.14±0.02 (range, 0 to 0.43) for the no compensation group. At follow-up study, the IIs were 0.22±0.02, 0.38±0.03, and 0.30±0.03, respectively.

Fig 3 compares the mean time after transplantation (segment-adjusted) between the three remodeling categories (P<.05). The overcompensation segments tend to occur early after transplantation, whereas the no compensation or shrinkage group tends to occur in segments late after transplantation.

View larger version (16K): [in this window] [in a new window]   Figure 3. Mean times after transplantation (Tx) of baseline IVUS studies are compared between the three different RIs: overcompensation (O), partial compensation (P), and no compensation/shrinkage (N). Overcompensation tends to occur early after transplantation, whereas no compensation/shrinkage tends to occur in lesions studied late after transplantation.

In 48 of the 75 patients, more than one segment was studied in the same vessel (Table). Overall, 52% of the patients showed concordance of the RI, ie, if all segments in the patient belong to the same remodeling category. However, if only patients in whom more than three segments were studied were included, 33% of the patients had concordance.

View this table: [in this window] [in a new window]   Table 1. Concordance or Discordance in Remodeling Category Among Coronary Segments

	Discussion

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This study addresses whether compensatory enlargement or shrinkage plays a role in the temporal development of transplant coronary artery disease. Serial IVUS shows that early after cardiac transplantation, a large proportion (49%) of the coronary segments with progression of intimal thickening have appropriate full compensatory dilation of the vessel wall. However, a substantial percentage (51%) of the coronary segments show less than full compensatory enlargement (29%) and even shrinkage (22%). This heterogeneous response occurs in segments that had substantially less than 30% lesion area stenosis (II). Segments with low baseline IIs do not have more compensatory dilation than segments with higher IIs. Therefore, we conclude that in transplant coronary artery disease, most segments do not remodel, as observed by Glagov et al⁵ in de novo atherosclerosis, and this disease is in part due to the failure of the vessel to compensatorily dilate or even shrink in the setting of intimal proliferation.

Compensatory enlargement is known to play a significant role in the early pathogenesis of native coronary artery disease. Glagov et al⁵ were the first to recognize this phenomenon in cross-sectional studies in pathology specimens. They found a highly significant association of artery size and plaque area in human coronary arteries that delayed the decrease in vascular lumen until the lesion occupied about 40% of the internal elastic lamina. Several IVUS studies have confirmed this "Glagov's phenomenon" in cross-sectional studies of patients comparing proximal and distal sites with the diseased area. In an IVUS study of native coronary arteries, Hermiller et al⁷ found a highly significant correlation between plaque volume and arterial size in arteries with a <30% stenosis. Losordo et al⁸ also used IVUS to study segments in diseased femoral arteries and compared these with a relatively disease-free segment more proximal in the same artery. They found that the increase in vessel size was proportionate to the amount of plaque at the same site. They further found that the enlargement of the artery was a focal response that did not affect the adjacent normal segments of the artery. Compensatory enlargement, however, does not always occur. Pasterkamp et al⁹ described shrinkage of vessel size in atherosclerotic femoral arteries. They analyzed human femoral arteries in postmortem and in vivo IVUS studies to assess how local changes in vessel size, together with plaque load, determine luminal narrowing in atherosclerotic arteries. They found that when lumen area stenosis was less than 25%, mainly compensatory enlargement was observed. When lumen area stenosis exceeded 25%, however, mainly a decrease of the internal elastic lamina area was observed, which is consistent with arterial wall shrinkage. Both compensatory enlargement and arterial wall shrinkage could be observed in one arterial segment. They concluded that arterial wall shrinkage is a paradoxical mechanism that may contribute to severe luminal narrowing of the atherosclerotic human femoral artery. Unfortunately, none of these studies observed the enlargement serially over time in the same subjects.

Remodeling with partial compensatory enlargement and shrinkage has also been observed in PTCA arteries. Kakuta et al¹⁵ used a rabbit animal model of iliac arteries that had undergone intervention and compared restenotic with nonrestenotic iliac arteries. They observed that the degree of vessel enlargement was more important than the degree of intimal proliferation to determine the chronic lumen size. In a similar rabbit animal model of femoral arteries that underwent intervention, Lafont et al¹⁶ demonstrated that late residual stenosis correlated with chronic constriction but not with neointimal-medial growth or adventitial growth. They concluded that chronic constriction occurs and is an important correlate of restenosis 3 to 4 weeks after balloon dilation in the injured rabbit femoral artery. Several groups have demonstrated in a porcine coronary restenosis model that shrinkage related to neointimal formation influenced the final size of the lumen much more than neointimal formation.^{17 18} These data are also in general agreement with human data. Preliminary results from serial IVUS/restenosis studies in native coronary artery disease show that a proportion of angioplasty sites may shrink as a result of the mechanical vascular injury.¹⁹ In a study by Kimura et al,²⁰ late lumen loss secondary to shrinkage, as studied by serial IVUS, occurred in 42% of lesions after balloon angioplasty or directional atherectomy. The absence of intimal proliferation in 40% of humans late after PTCA has been described in an autopsy study of 20 patients with restenosis, suggesting that constriction plays a major role in this process.²¹

The above data regarding remodeling suggest that shrinkage occurs late in native atherosclerosis but is a much more common phenomenon after PTCA. Our observation in transplant coronary artery disease is more consistent with the data in the PTCA literature, suggesting that in both populations, the vessels are exposed to substantial injury (immune versus mechanical) and shrinkage is a universal response.

Currently, little is known about the mechanisms of remodeling or lack of remodeling in the transplant coronary arteries. An increase in wall shear stress secondary to an increase in blood flow velocity around intimal thickening may stimulate endothelial cell–dependent vasodilatation and subsequent remodeling.^{22 23 24 25} Coronary blood flow in response to acetylcholine is impaired in transplant patients secondary to endothelial dysfunction. This may contribute to the impairment of compensatory dilation in the conduit vessels.²⁶ Vascular remodeling entails the reconstruction of the extracellular matrix scaffolding. Endothelial cells, vascular cells, and extracellular components interact closely, and their relation ultimately determines the geometry of the blood vessel.²⁷ This process is a homeostatic balance between synthesis and proteolysis, which might be easily disturbed by factors such as rejection. In the pathogenesis of transplant coronary artery disease, the endothelium seems to play a pivotal role by releasing or activating substances that influence the growth, death, and migration of cellular elements or the composition of the extracellular matrix. Endothelial dysfunction occurs at an early stage and precedes intimal thickening.²⁸ This may impair the capability of the arterial wall to undergo compensatory enlargement. Other studies have shown that smooth muscle dysfunction can also occur early after transplantation.²⁹ It is therefore possible that the mechanisms involved in causing intimal proliferation, by affecting the vascular wall, also influenced the process of remodeling. The fact that we find such a variety of vascular remodeling, ranging from shrinkage to partial compensation to overcompensation, could be a reflection of how the vessel is affected by immune mechanisms in the complex pathogenesis of transplant coronary artery disease.

Study Limitations
Our study includes only those segments that have a 10% increase in IA between the two serial IVUS studies, because the objective of our study is to define whether compensatory enlargement occurs with progressive intimal thickening. Thus, we can define the role of remodeling in the pathogenesis of transplant coronary artery disease. Studies of those segments without progression may help to define the overall remodeling process in transplant coronary artery disease. However, given the cross-sectional nature of this present study, it is difficult to draw definitive conclusions from this heterogeneous group. This study does not attempt to conclude that intimal thickening is causative in the remodeling process, which is most likely multifactorial. An ongoing prospective study will address all vessel segments in detail and thus define the nature of the remodeling process in this disease.

The amount of disease present in our patients is quite modest (mean II, <40%). Therefore, our conclusions are valid only in the early stages of this disease. However, the presence of partial compensation and shrinkage even this early suggests that lack of remodeling plays a central role in the pathogenesis of transplant coronary artery disease.

This study was performed on a per-segment basis, and no attempt was made to correlate other clinical characteristics with the RI, given the discordance between segments within the same patient.

Conclusions
In this study, serial IVUS shows that early after cardiac transplantation, a large proportion of the coronary segments with progression of intimal thickening have compensatory dilation of the vessel wall. A substantial number of coronary segments, however, show little or no compensatory enlargement. The progression of luminal narrowing in transplant patients may be due in part to the lack of compensatory dilation or shrinkage of the artery over time.

	Selected Abbreviations and Acronyms

 

IA = intimal area IA = change in intimal area II = intimal index IVUS = intravascular ultrasound LA = luminal cross-sectional area PTCA = percutaneous transluminal coronary angioplasty RI = remodeling index TA = total cross-sectional vessel area TA = change in total area

	Acknowledgments

 
Dr Yeung is supported by NIH CIDA grant K08-HL-02787. We thank Dr Richard Popp for advice and review of the manuscript and Ann Schwarzkopf for assistance in collection of the ultrasound data.

Received April 8, 1996; revision received October 8, 1996; accepted October 14, 1996.

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