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(Circulation. 1996;93:457-462.)
© 1996 American Heart Association, Inc.

Articles

Early Endothelial Dysfunction Predicts the Development of Transplant Coronary Artery Disease at 1 Year Posttransplant

Stacy F. Davis, MD; Alan C. Yeung, MD; Ian T. Meredith, MBBS, PhD; François Charbonneau, MD; Peter Ganz, MD; Andrew P. Selwyn, MD; Todd J. Anderson, MD

From the Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Stacy F. Davis, MD, Brigham and Women's Hospital, Cardiovascular Division, 75 Francis St, Boston, MA 02115.

	Abstract

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Background Accelerated coronary arteriosclerosis is the major obstacle to long-term survival after cardiac transplantation. Endothelial dysfunction is common early posttransplant. The relationship between early endothelial dysfunction and the development of allograft arteriosclerosis has not been analyzed serially with intravascular ultrasound in the same patients. We hypothesized that an early constrictor response to acetylcholine, indicative of endothelial dysfunction, may predict the development of transplant coronary arteriosclerosis.

Methods and Results Endothelium-dependent vasomotion was assessed early posttransplant in 20 patients by serial intracoronary acetylcholine infusion, and the percent change in diameter was measured by quantitative angiography. The development of arteriosclerosis was studied by use of intravascular ultrasound in the same 20 patients by quantifying the changes in intimal index (Ii) and maximal intimal thickness [Mt] of 46 matched coronary segments between initial and 1-year follow-up studies. Coronary segments with endothelial dysfunction (constriction 5%; n=23) demonstrated a significantly greater increase in mean Ii and Mt by 1 year posttransplant compared with segments with normal endothelial function (n=23) (Ii=7±2% versus 2±1% [P<.05] and Mt=140±40 versus 50±20 µm [P<.05]). No other parameters examined predicted the development of allograft arteriosclerosis in the initial year posttransplant.

Conclusions Paired studies that used intravascular ultrasound showed that early endothelial dysfunction predicts the development of allograft arteriosclerosis during the initial year posttransplant. This early pathophysiological feature is likely an important marker that could be useful in therapeutic trials.

Key Words: endothelium • acetylcholine • ultrasonics • transplantation • atherosclerosis

	Introduction

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Accelerated transplant coronary arteriosclerosis is the major obstacle to long-term survival after cardiac transplantation.¹ This progressive disease limits recipient survival because it results in diffuse concentric tapering and pruning of the distal vasculature in addition to focal obstructions of medium and small arteries with rare collaterals.² Annual coronary angiography is performed for diagnostic and surveillance purposes because patients may remain asymptomatic until they develop heart failure, cardiac arrhythmia, or sudden death.³ Angiographic studies have documented transplant coronary arteriosclerosis in 40% to 50% of patients by 5 years posttransplant but are insensitive for early detection of this disease.^{4 5} Intimal thickening is commonly detected by IVUS at 1 year posttransplant, suggesting that development of allograft arteriosclerosis begins very early after transplantation.⁶ Although the etiology of this disease remains unclear, immune and ischemic mechanisms of endothelial injury in the setting of hyperlipidemia are likely to play a role.^{7 8}

Endothelial dysfunction is an early and characteristic feature of both native and allograft coronary artery disease.^{9 10 11 12} It would be helpful if this pathophysiological marker could be used in transplant patients to detect early disease activity before the occurrence of significant vessel wall disease. Thus, the aim of the present study was to identify early endothelial dysfunction in transplant recipients and correlate this with the later development of intimal pathology. We hypothesized that early evidence of endothelial dysfunction after cardiac transplantation would predict the development and subsequent progression of accelerated allograft arteriosclerosis.

	Methods

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Patient Population
One hundred thirty-three patients underwent cardiac transplantation at Brigham & Women's Hospital between 1989 and 1993. This investigation aimed to describe the natural history of endothelial function in the transplant population free of acute postoperative complications and its relation to the development of intimal thickening during the initial year posttransplant. Therefore, 49 patients were excluded from endothelial function testing because of early postoperative complications that precluded catheterization (eg, hemodynamic instability, renal dysfunction, infection, multisystem organ failure, stroke), 30 because of failure to obtain consent, 10 owing to early mortality, 8 because of technical features discovered at catheterization (coronary arteries too small to cannulate and examine with IVUS), and 1 owing to early rejection. Fifteen patients were excluded because of failure to undergo follow-up IVUS study. Finally, 20 patients with a completely uncomplicated clinical course underwent catheterization and vasomotor function testing at a mean of 16±1 days posttransplantation and paired serial IVUS studies at the time of initial endothelial function testing and 1 year later immediately after annual coronary angiography (371±4 days posttransplant). Those patients excluded did not differ in terms of demographic characteristics or other clinical features from those enrolled in the study.

All patients were treated with triple immunosuppression (cyclosporine, prednisone, and azathioprine) and two patients in the study group received OKT3 induction therapy. The clinical characteristics of each patient were obtained, including the pretransplant diagnosis, age, and sex of the recipient and donor, graft ischemic time, pretransplant and posttransplant risk factors for native coronary atherosclerosis, cytomegalovirus serologies, serum lipid profiles, posttransplant hyperlipidemic therapy, and the number of treated rejection episodes.

Study Protocol
Written informed consent was obtained from patients before cardiac catheterization in accordance with the guidelines established by the Committee for the Protection of Human Subjects. Long-acting vasoactive medications, including calcium channel blockers, ß-blockers, nitrates, and angiotensin-converting enzyme inhibitors, were discontinued at least 18 hours before the baseline catheterization. After the left heart catheterization was performed, patients were enrolled in the study if their LAD was free of any sites with >50% stenosis.

Intracoronary Infusions
Serial intracoronary infusions were performed according to an established protocol: (1) control infusion (dextrose 5% in water [D5W]); (2) serial 2.5-minute infusions of the endothelium-dependent vasodilator acetylcholine (Miochol, Iolab Pharmaceuticals) with final estimated intracoronary concentrations of 10^-8, 10^-7, and 10^-6 mol/L (based on assumed LAD blood flow of 80 mL/min)¹³ ; (3) 5-minute repeat control infusion of D5W; and (4) 3-minute infusion of the endothelium-independent vasodilator nitroglycerin at 16 µg/min.⁹ During each infusion, blood pressure, heart rate, and ECG were continuously monitored. Cineangiographic images were obtained after each infusion.

IVUS
After removal of the infusion catheter, the intracoronary imaging system was passed into the LAD. Sublingual nitroglycerin (0.4 mg) was given before insertion of the catheter. The imaging system consisted of a 30-MHz transducer and rotating mirror enclosed within an acoustic housing at the tip of a 4.3F, 135-cm-long catheter (CVIS Inc).¹⁴ The imaging catheter was advanced as far distal as possible into the LAD. Contrast cineangiography was used to record each IVUS catheter position. A map was created by printing a video image of the LAD on heat-sensitive paper. Each IVUS position and its relationship to adjacent anatomic landmarks, such as diagonal or septal perforator branches, was identified by review of video loops and clearly marked on the paper for subsequent reference. A second IVUS study, performed 1 year later, used this map and angiographic landmarks to carefully match catheter positions.

Analysis
IVUS Measurements
IVUS images were recorded on Super VHS tape and digitized into a Macintosh computer for quantitative analysis. Forty-six coronary segments with matched IVUS data from serial studies were analyzed. Matching of segments was confirmed by review of the angiogram and IVUS catheter position maps.

The ultrasound images at each position were assessed by two observers blinded to the results of the acetylcholine infusion. The lumen and lumen/intima interface were planimetered, intimal thickening was measured at eight radial chords, and the maximal intimal thickness (Mt) was recorded. Development of intimal pathology was quantified by measuring the change in intimal index (Ii) [Ii=intimal area/(intimal area+luminal area)] and Mt (Mt) of the matched coronary segments between initial and 1-year follow-up studies. The results of three digitized frames at each position were averaged to obtain the data for that segment. Segments were included if they had analyzable matched ultrasound data and baseline vasomotion data. Progression of intimal pathology between initial and 1-year follow-up IVUS studies was defined as a mean Ii 5% or a mean Mt 150 µm.

Quantitative Coronary Angiography
Technically suitable single-plane angiographic images were selected for computer analysis based on a previously validated method.^{10 15} The variability of this method is <4%.^{16 17} An automated edge-detection program was used to search densities and seek inflection points, measuring the diameter of the vessel along the selected segment (Quantum IC Software, ImageComm). To ensure accurate matching of coronary structure and vasomotion, quantitative angiographic measurements from the immediate region (4 to 5 mm) on both sides of each IVUS position were used to assess endothelial function. The sites of correlation were at least 1 cm apart within the artery.

Results of endothelial function testing with acetylcholine were analyzed on a per patient and a per segment basis. Patients were categorized as constrictors (endothelial dysfunction) if at least one coronary segment demonstrated 5% constriction to intracoronary acetylcholine infusion and as dilators (normal endothelial function) if all vessel diameters measured remained unchanged or dilated. Similarly, coronary segments that demonstrated 5% constriction in response to intracoronary acetylcholine infusion were defined as constrictors, whereas those segments that remained unchanged or dilated were categorized as dilators.

Statistics
For the per patient analysis, differences in the demographic and clinical characteristics between groups of patients were analyzed by use of unpaired t tests. A univariate analysis of the individual clinical parameters was performed. For the per segment analysis, proportions of segments were analyzed by use of Fisher's exact test. Statistical significance was defined as a two-sided probability value less than .05. All data are expressed as mean±SE.

	Results

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Patient Analysis: Baseline Demographics and Changes in Clinical Characteristics
The mean age of the 20 study patients at cardiac transplantation was 51±2 years (range, 31 to 62 years) and mean donor age was 28±3 years (range, 11 to 54 years). The pretransplant diagnosis was coronary artery disease in 13 (65%) of the patients and non–ischemic cardiomyopathy in 7 (35%). Pretransplant risk factors for native coronary atherosclerosis were distributed as follows: tobacco use, 13 (65%); diabetes mellitus, 7 (35%); family history of premature coronary atherosclerosis, 6 (30%); hypertension, 6 (30%); and hyperlipidemia, 6 (30%). Twelve patients (60%) were categorized as constrictors and 8 patients (40%) were classified as dilators on the basis of their response to acetylcholine infusion. Two patients showed heterogeneous responses to acetylcholine, and these patients were classified as constrictors. There was no significant difference in baseline demographics of the constrictors and dilators (Table 1). Changes in clinical characteristics of the constrictors and dilators during the initial year posttransplant were examined. As expected, serum cholesterol, triglycerides, and body surface area increased in both groups of patients. However, the change in these parameters did not differ significantly between groups (Table 2).

View this table: [in this window] [in a new window]   Table 1. Patient Demographics at Baseline

View this table: [in this window] [in a new window]   Table 2. Changes in Clinical Characteristics During First Year Posttransplant

Patient Analysis: Coronary Structure and Endothelial Function
The mean percent diameter change in response to acetylcholine of the 12 constrictors was -22.1±3.3% and the mean response of the 8 dilators was 7.9±2.0% (P<.01). There was no significant difference between groups in response to infusion of the endothelium-independent agonist nitroglycerin (mean diameter change=12.0±3.9% versus 13.5±4.2% for constrictors versus dilators; P=NS).

The development of intimal thickening during the initial year posttransplant was first analyzed on a per patient basis. There was no significant difference in the baseline intimal thickness of the 12 constrictors compared with the 8 dilators. There was a trend showing development of more intimal thickening among constrictors compared with dilators during the initial year posttransplant (Ii=9±3% versus 4±1%, respectively, P=.10; Mt=160±40 versus 70±20 µm, respectively, P=.09) (Table 3).

View this table: [in this window] [in a new window]   Table 3. Patient Analysis (n=20): Early Endothelial Function and Development of Intimal Pathology

In the present longitudinal study, early endothelial dysfunction (16±1 days posttransplant) tended to be associated with angiographic evidence of allograft arteriosclerosis at 1 year posttransplant. Seven (58%) of 12 patients with a constrictor response to acetylcholine early posttransplant demonstrated angiographic evidence of allograft arteriosclerosis at 1 year posttransplant (tapering of the distal LAD and/or tertiary vessel loss), in contrast to 1 (13%) of 8 patients with a dilator response (P=.05).

Segment Analysis: Coronary Structure and Endothelial Function
Because segmental heterogeneity may occur within a patient's arteries and is characteristic of arteriosclerosis, analyses and correlation of coronary structure and endothelial function were also performed on a per segment basis. A total of 46 coronary segments were analyzed. Twenty-three segments (50%) demonstrated early endothelial dysfunction (constriction to acetylcholine) with a mean diameter change of -23.9±2.6% compared with a mean diameter change of 7.1±1.5% (P<.01) for the 23 (50%) segments with preserved endothelial function. There was no significant difference in the response of acetylcholine constrictor and dilator segments to infusion of the endothelium-independent agonist nitroglycerin (mean diameter change=10.2±3.3% versus 13.4±2.6% for constrictors versus dilators).

There was no significant difference in baseline intimal thickness of the two groups of segments. The proportions of segments that demonstrated progression of intimal thickening between initial and 1-year follow-up IVUS studies were analyzed. Progression of Ii (Ii5%) occurred in 10 (43%) of 23 constricting segments and 5 (22%) of 23 dilators. Progression of Mt (Mt150 µm) occurred in 9 (39%) of 23 constrictors and 4 (17%) of 23 dilating segments.

We then examined the percent change in mean Ii and Mt of the constricting and dilating segments. The constricting segments demonstrated a significantly greater change in mean Ii (Ii) and Mt (Mt) by 1 year posttransplant compared with segments that dilated in response to acetylcholine (Ii=7±2% for constrictors versus 2±1% for dilators, P<.05; Mt=140±40 µm for constrictors versus 50±20 µm for dilators, P<.05) (Table 4).

View this table: [in this window] [in a new window]   Table 4. Segment Analysis (n=46): Early Endothelial Function and Development of Intimal Pathology

In this segment analysis, only early posttransplant endothelial dysfunction predicted the development of intimal thickening by IVUS. The development of intimal thickening was not predicted by donor characteristics, graft ischemic time, recipient risk factors for native coronary atherosclerosis, the number of treated rejection episodes, or the immunosuppressive regimen.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This longitudinal study has demonstrated that impaired endothelium-dependent coronary vasodilation in response to acetylcholine is common early after cardiac transplantation. Coronary artery segments with early endothelial dysfunction developed more intimal thickening by 1 year posttransplant than did segments with preserved endothelial function. We have shown for the first time in transplant recipients that constriction in response to acetylcholine, which is indicative of endothelial dysfunction, is associated with accelerated allograft coronary arteriosclerosis.

Allograft arteriosclerosis is insidious and progressive, begins early after transplantation, and is the chief cause of late mortality or retransplantation among adult and pediatric allograft recipients.^{18 19} Pathological studies²⁰ demonstrated a diffuse myointimal proliferative process that affects epicardial vessels as well as the coronary microvasculature. In the earliest stages of development, this vasculopathy is often difficult to detect by angiography because the presence of intimal atheroma may be masked by compensatory vascular growth and dilation due to enlargement of the medial and adventitial layers.²¹ IVUS has become the primary modality for assessment of this disease, although the long-term significance of early intimal thickening is unclear.²² Identification of patients early posttransplantation who are at increased risk of accelerated allograft coronary arteriosclerosis has not been possible.

The coronary endothelium releases nitric oxide, which modulates vascular tone and permeability, inhibits platelet aggregation and smooth muscle cell proliferation, and regulates leukocyte adhesion.^{23 24} Abnormalities in the L-arginine–nitric oxide system likely play a role in the pathogenesis of native and allograft coronary artery disease.^{9 10 12} The coronary vasomotor response to acetylcholine is mediated via nitric oxide, and an abnormal response (constriction) is one hallmark of impaired endothelial function.²⁵ Impaired coronary vasodilation in response to intracoronary acetylcholine infusion was described initially in epicardial vessels at 1 and 2 years after cardiac transplant.¹¹ Treasure and colleagues²⁶ extended these observations by demonstrating that endothelial dysfunction also occurred in the microvasculature of transplant recipients.

Endothelial dysfunction early after transplantation is a common feature of allograft arteriosclerosis that may be related to immune or ischemic endothelial injury in the setting of hyperlipidemia.^{7 11} Hruban and coworkers²⁷ demonstrated T-lymphocyte–mediated endothelial activation in patients with this disease, suggesting that cellular immunity may promote endothelial injury. Cytotoxic B-cell antibodies, anti-HLA antibodies, and anti-endothelial antibodies also were demonstrated in patients with allograft arteriosclerosis.^{28 29 30 31} In addition to these immunologic observations, ischemia and reperfusion produced endothelial dysfunction in a canine cardiac allograft model, and peritransplant ischemic injury predicted the development of allograft arteriosclerosis in human recipients.^{32 33} This experimental evidence provides the rationale for our study of early posttransplant endothelial function.

We recently demonstrated³⁴ that endothelial dysfunction occurred in approximately two thirds of patients within 1 month of transplant and was not predicted by donor or recipient demographics. The long-term significance of these findings has not been addressed previously. In another study,³⁵ we tested endothelial function in 38 patients at 1 year posttransplant and found that the acetylcholine constrictors and dilators did not differ in the number of ischemic events over a 4-year period. IVUS data were not available in these patients.

The present longitudinal study used serial paired IVUS studies as a more rigorous measure of the development of allograft arteriosclerosis. Coronary segments with early endothelial dysfunction demonstrated a significantly greater increase in mean Ii and Mt by 1 year posttransplant compared with segments with preserved coronary vasomotion. Early endothelial dysfunction was the only predictor of the development of intimal thickening during the initial year posttransplant and may serve as a marker that could identify patients at increased risk of allograft coronary arteriosclerosis.

Study Limitations
The coronary vasodilator response to acetylcholine was the only measure of endothelial function examined in the present study. We chose to focus on this response because it is an accepted early measure of endothelial function, reflects nitric oxide–dependent pathways, and is reproducible.³⁶ Other manifestations of endothelial injury, such as impaired leukocyte–endothelial cell interactions, platelet hyperaggregability, and altered hemolytic and fibrinolytic pathways also may occur posttransplant, but these were not evaluated.^{37 38 39}

The present longitudinal study matched early posttransplant coronary acetylcholine responses with serial IVUS images from a limited number of patients. Because segmental heterogeneity may occur within a patient and intimal thickening may not be uniformly distributed along the entire length of an artery, we analyzed endothelial function and coronary structure on a per segment basis. The length of thickening may correlate better with endothelial function than with the intimal pathology at a single position, but current technical limitations preclude accurate measurements of an entire region. The IVUS data presented in this study were based on images from the proximal one half to two thirds of the LAD because of limitations of the imaging technology. Other coronary vessels were not assessed because allograft arteriosclerosis is a diffuse process that tends to affect the entire coronary tree.⁴⁰

Some intimal thickening may have developed between the time of cardiac transplantation and the initial IVUS study (16±1 days posttransplant). For the purpose of the present study, we assumed that the early posttransplant IVUS study accurately reflected baseline intimal pathology. Since the baseline Ii and Mt of the constrictor and dilator segments did not differ significantly, this did not influence our analysis.

We cannot exclude the possibility that constrictors have more baseline intimal thickening than dilators. Part of the early endothelial dysfunction observed may be related to donor-acquired atherosclerosis. However, the majority of patients with early endothelial dysfunction have no intimal thickening, and the contribution of early endothelial dysfunction due to cardiac transplantation cannot be underestimated.⁶

Conclusions
With the use of IVUS, the present longitudinal study of cardiac transplant patients has shown that early endothelial dysfunction predicts the development of allograft arteriosclerosis during the initial year posttransplant. Endothelial dysfunction is an early pathophysiological feature of transplant coronary arteriosclerosis and is likely an important marker and potential target for therapeutic interventions.

	Selected Abbreviations and Acronyms

 

Ii = intimal index IVUS = intravascular ultrasound LAD = left anterior descending coronary artery Mt = maximal intimal thickness

	Acknowledgments

 
This work was supported by the Cardiovascular Division of Brigham & Women's Hospital (Dr Davis); NHLBI clinician-investigator development award 1 K08 HL-02787 (Dr Yeung); National Heart Foundation of Australia Ralph Reader overseas research fellowship (Dr Meredith); NHLBI research career development award 1 K04 HL-02566 and NIH P01-HL48743 (Dr Ganz); NHLBI R01 HL-38780-05 (Dr Selwyn); and a clinical fellowship of the Alberta Heritage Foundation for Medical Research (Dr Anderson).

We wish to thank the dedicated research fellows and cardiologists who performed these catheterization studies over the past 4 years. We also wish to thank the technical and nursing staff of the cardiac catheterization laboratory who made these studies possible.

Received April 3, 1995; revision received August 7, 1995; accepted September 18, 1995.

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