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Circulation. 1995;92:182-190

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(Circulation. 1995;92:182-190.)
© 1995 American Heart Association, Inc.

Articles

Influence of Intimal Thickening on Coronary Blood Flow Responses in Orthotopic Heart Transplant Recipients

A Combined Intravascular Doppler and Ultrasound Imaging Study

Eugene A. Caracciolo, MD; Thomas L. Wolford, MD; R. Dent Underwood, MD; Thomas J. Donohue, MD; Richard G. Bach, MD; Leslie W. Miller, MD; Morton J. Kern, MD

From the Division of Cardiology, Department of Cardiology, St Louis University Hospital, St Louis, Mo.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Background Intravascular ultrasound imaging detects epicardial intimal thickening in the majority of heart transplant recipients with angiographically normal epicardial coronary arteries. Although coronary artery vasoreactivity is abnormal after cardiac transplantation, intimal thickening does not appear to affect conduit vessel responses. However, the effect of intimal thickening on both conduit and resistance vessel responses, as measured by changes in volumetric coronary blood flow (CBF), is unknown.

Methods and Results Epicardial coronary artery conductance and microvascular resistance vessel responses were studied after intracoronary adenosine and nitroglycerin administration in 36 orthotopic heart transplant recipients 1 month to 7 years after transplantation. Sequentially measured coronary flow average peak velocity ([APV, cm/s] 0.018 in Doppler guide wire) and epicardial luminal cross-sectional area ([CSA, mm2] 4.3F 30-MHz ultrasound catheter) data were obtained at baseline and during peak hyperemia after administration of 12 to 18 µg IC adenosine and 150 to 200 µg IC nitroglycerin. Volumetric CBF (mL/min) was calculated as CBF=APV (cm/s)xCSA (mm2)x60 seconds/1 minx1 cm2/100 mm2x0.5. Measurements were made from a discrete position in the proximal left anterior descending (LAD) artery (n=22), mid-LAD artery (n=7), proximal circumflex artery (n=6), and proximal right coronary artery (n=1). Intimal thickening was present in 19 of 32 patients (60%). Both adenosine and nitroglycerin increased APV (from 18.9±4.9 to 56.0±11.5 cm/s for adenosine and from 20.2±5.3 to 49.1±11.5 cm/s for nitroglycerin; both P<.05). Coronary flow velocity reserve was significantly higher for adenosine compared with nitroglycerin (3.1±0.6 versus 2.5±0.7, respectively; P<.001). Epicardial luminal CSA was unchanged during adenosine hyperemia compared with baseline (17.4±3.8 versus 17.3±4.0 mm2, respectively; P=NS) but was significantly greater during nitroglycerin hyperemia compared with baseline (18.7±3.8 versus 17.3±4.0 mm2, 6.2±3.6% change; P<.05). Baseline CBF was similar before drug administration. Hyperemic adenosine and nitroglycerin CBF responses (297±99 and 276±87 mL/min, respectively; P=NS) and CBF reserve (3.0±0.7 and 2.7±0.7, respectively; P=NS) were not significantly different. Importantly, intimal thickening did not diminish resting or hyperemic APV, coronary flow velocity reserve, luminal CSA, CBF, or CBF reserve responses.

Conclusions In this study of angiographically normal heart transplant recipients, epicardial intimal thickening does not diminish conduit and resistance vessel responses during endothelial-independent vasodilator administration.


Key Words: blood flow • transplantation • adenosine • nitroglycerin


*    Introduction
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 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
The development of transplant coronary arteriopathy is perhaps the major limiting factor in the long-term survival of orthotopic heart transplant recipients.1 2 3 4 Angiographic abnormalities in the epicardial coronary arteries are present in approximately 50% of patients by 5 years after transplantation.5 6 Although angiography remains the standard for coronary imaging, it is a relatively insensitive technique that correlates poorly with the degree of allograft vasculopathy documented by pathological examination.7 8 2D IVUS imaging of angiographically normal epicardial coronary arteries in heart transplant recipients has demonstrated epicardial intimal thickening in the majority of patients studied at least 1 year after transplantation.9 10 The functional significance of transplant arteriopathy has been evaluated by measuring coronary vasoreactivity after administration of the endothelium-dependent vasodilators acetylcholine and substance P and the endothelium-independent vasodilators nitroglycerin, adenosine, and papaverine.10 11 12 13 14 15 16 17 18 Intact epicardial vasodilatory responses after nitroglycerin administration10 12 14 15 17 and resistance vessel responses after adenosine administration13 have been reported in both angiographically normal and abnormal transplant patients. Abnormal epicardial conduit and microvascular resistance vessel responses have been demonstrated after endothelium-dependent vasodilator administration14 15 16 17 18 in angiographically normal and abnormal transplant patients. However, intimal thickening, detected by IVUS imaging, does not affect epicardial vasoreactivity after nitroglycerin10 or in long-term heart transplant recipients after acetylcholine administration.11 Although intimal thickening does not appear to affect conduit vessel responses, it is unknown whether intimal thickening affects resistance vessel responses or CBF responses that reflect the integration of both conduit and resistance vessel reactivity.

We hypothesized that preserved endothelium-independent vasodilator responses in conduit and resistance vessels, as measured by changes in CBF, are present despite the presence of intimal thickening. Therefore, the purpose of this study was to evaluate whether intimal thickening detected by IVUS imaging affects CBF responses in angiographically normal heart transplant recipients.


*    Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Thirty-six orthotopic heart transplant recipients, 28 men (mean age, 48±12 years; range, 24 to 63 years) and 8 women (mean age, 51±9 years; range, 35 to 62 years) with angiographically normal coronary arteries undergoing routine annual right and left heart catheterization, coronary arteriography, and right ventricular endomyocardial biopsy, were studied (Table 1Down). Eight patients were studied within 30 days as part of their initial evaluation after transplantation, and 11 and 17 patients were studied at 1 year and 2 or more years, respectively. Angiographic transplant arteriopathy was excluded by Stanford University criteria.6 All patients were managed with a three-drug immunosuppressive regimen that included cyclosporine, azathioprine, and prednisone. Antilymphocyte antibody was not used prophylactically. Medications, including calcium channel and ß-adrenergic blockers and angiotensin-converting enzyme inhibitors, were held for 24 hours before the procedure. This investigation was approved by the Human Research Committee of St Louis University Health Sciences Center. All subjects provided informed written consent before participation.


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  		Table 1. Patient Characteristics

Study Protocol
All patients received diphenhydramine (25 mg IV) and diazepam (2 to 4 mg IV) before the catheterization procedure. Sublingual or intracoronary nitroglycerin was not administered during diagnostic coronary angiography. After cardiac catheterization and right ventricular endomyocardial biopsy, sequential measurements of coronary flow velocity with a Doppler guide wire and epicardial luminal CSA by 2D IVUS imaging was obtained in the resting state and during maximal coronary hyperemia after serial administration of intracoronary adenosine and nitroglycerin. Each patient received 10 000 U IV heparin before the study protocol.

Coronary Flow Velocity Measurements
All CBF velocity measurements were obtained with a Doppler ultrasound imager–tipped angioplasty guide wire (FloWire, Cardiometrics, Inc) as previously described.19 20 21 The FloWire is a 175-cm-long, flexible, steerable 0.018-in angioplasty guide wire equipped with a 12-MHz piezoelectric ultrasound transducer integrated into the tip. Coronary flow velocity up to 4 m/s can be recorded without aliasing by the forward directed ultrasound beam (27° angular beam divergence width). The Doppler signals are processed by on-line fast-Fourier transformation, which provides a scrolling real-time spectral gray-scale display. Doppler guide wire flow velocity measurements demonstrate an excellent correlation with electromagnetic flow velocity in straight- and curved-tube models.21 The Doppler guide wire has been used without complications at our institution in more than 700 studies of human coronary arteries.

The Doppler guide wire was advanced through an 8F guiding catheter equipped with a standard angioplasty Y-connector into the study vessel, which was the proximal LAD artery (n=22), mid-LAD artery (n=7), proximal circumflex artery (n=6), or proximal right coronary artery (n=1). Flow velocity parameters were measured at baseline and during maximal hyperemia after 12 to 18 µg IC of bolus adenosine. Mean arterial pressure and heart rate were continuously recorded before and during the hyperemic response. After return to baseline conditions, flow velocity data were again measured at baseline and during maximal hyperemia after 150 to 200 µg IC bolus of nitroglycerin (Figs 1Down and 2Down). At least 5 minutes separated acquisition of the adenosine and nitroglycerin flow velocity measurements. The order of drug administration was not randomized. The FloWire position was documented by fluoroscopy so that subsequent IVUS imaging data could be acquired in the reference segment of the study vessel.



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  		Figure 1. Intracoronary Doppler FloWire velocity measurements (top) and 2D IVUS coronary images (bottom) from the midportion of the LAD coronary artery in a 51-year-old man 5 years after orthotopic heart transplantation. Baseline (left) and peak hyperemic (right) responses to 12 µg IC adenosine are recorded. The baseline APV of 16.7 cm/s increased to 55.0 cm/s. Coronary flow velocity reserve was 3.3. Epicardial conductance vessel CSA (mm2) was constant during maximal hyperemia. Volumetric CBF increased from 101 mL/min at baseline to 328 mL/min during peak hyperemia. I indicates intimal thickening. Velocity scale=0 to 160 cm/s; imaging scale=0.5 mm per division.



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  		Figure 2. Intracoronary Doppler FloWire velocity measurements (top) and 2D IVUS coronary images in response to nitroglycerin (bottom) in the same patient described in Fig 1Up. The baseline APV of 14.5 cm/s increased to 44.2 cm/s. Coronary flow velocity reserve was 3.0. The baseline epicardial CSA of 19 mm2 increased to 20.5 mm2 (8% change) during peak hyperemia. Volumetric CBF increased from 83 mL/min at baseline to 272 mL/min during peak hyperemia. I indicates intimal thickening. Format as in Fig 1Up.

Coronary Flow Velocity Signal Analysis
Flow velocity parameters were automatically derived by a previously validated integrated custom software program. Digitized spectral peak velocity waveforms from two cardiac cycles were averaged to compute the APV (cm/s). Coronary flow velocity reserve was computed as the ratio of hyperemic to resting APV.

2D Ultrasound Coronary Image Acquisition and Analysis
Intracoronary ultrasound imaging was performed with a 4.3F ultrasound catheter (CVIS, Inc), which has a fixed 30-MHz transducer and an 1800-rpm rotating mirror assembly enclosed within an acoustic housing at the tip. At a focal length of between 1.5 and 4.5 mm, axial resolution is approximately 150 µm.9 Real-time images are displayed on a video monitor. Time-gain compensation, compression, and reject settings were adjusted to yield a balanced gray-scale video display for optimal visualization of the lumen–vessel wall interface.

IVUS imaging was performed immediately upon completion of the flow velocity measurements. The ultrasound catheter was advanced into the study vessel over a 0.014-in guide wire. The catheter was positioned about 0.5 to 1.0 cm distal to the position of the FloWire tip at which velocity measurements were obtained, permitting imaging at the site of flow velocity measurements. IVUS images were obtained at baseline and during maximal hyperemia (15 seconds) after administration of 12 to 18 µg IC adenosine and 150 to 200 µg IC nitroglycerin (Figs 1Up and 2Up). At least 5 minutes separated acquisition of the adenosine and nitroglycerin images.

Real-time images were recorded on -in VHS videotape for subsequent off-line analysis. Determination of coronary luminal CSA was performed with an IBM-compatible 386 PC interfaced to a digitizing tablet (Summagraphics) using custom-developed software. Since the real-time 2D IVUS images were not gated to the cardiac cycle, planimetry with cursor-driven calipers was performed on four random baseline and four hyperemic frames, providing an average area for each study condition.

Epicardial Coronary Intimal Thickening
Epicardial coronary intimal thickening was defined by Stanford University criteria22 as ultrasound evidence of a three-layered vessel wall appearance over more than 180° of the lumen circumference. This qualitative definition corresponds to Stanford University class II and class IV intimal thickening and does not include measurement of the intimal thickening. In cases where epicardial intimal thickening was absent, luminal CSA was measured by planimetering the lumen–vessel wall interface. In cases in which epicardial intimal thickening was present, luminal CSA was measured by tracing the leading edge of the hypoechoic medial band and therefore included the intimal thickening in the luminal CSA determination.

Calculation of Volumetric CBF
As validated by Doucette et al,21 volumetric CBF was calculated as CBF=CSA (mm2)xAPV (cm/s)x60 s/1 minx1 cm2/100 mm2x0.5. The factor 0.5 was applied for an assumed parabolic velocity profile.21 Volumetric CBF reserve was computed as the ratio of hyperemic to resting CBF.

Statistical Analysis
All comparisons of baseline and hyperemic responses after adenosine and nitroglycerin administration were made by a one-factor ANOVA for repeated measures. Comparisons of the percent change in the hyperemic response between adenosine and nitroglycerin and comparisons of coronary flow velocity and blood flow reserves between adenosine and nitroglycerin were analyzed by a two-tailed, paired Student's t test.

Comparisons among baseline values, hyperemic responses, and CBF reserves stratified by time after transplantation were each analyzed by a one-way ANOVA with a Scheffé's test for comparison of the means. Comparisons between baseline values, hyperemic responses, and CBF reserves stratified by the presence or absence of intimal thickening were each analyzed by a two-tailed, unpaired Student's t test. Comparisons of baseline and hyperemic responses after adenosine and nitroglycerin administration stratified by the presence or absence of intimal thickening were analyzed by a two-tailed, unpaired Student's t test.

Values are expressed as mean±SD, and a probability value of P<.05 was considered to be statistically significant.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
*Results
down arrowDiscussion
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Patient Characteristics
Of the 36 orthotopic heart transplant recipients studied, all had angiographically normal epicardial coronary arteries. In 4 patients, technically adequate IVUS images were not obtained. Intimal thickening was present in 19 of 32 patients (60%). In the 6 patients studied within 30 days of transplantation who had an acceptable IVUS study, 5 had no evidence of intimal thickening. Conversely, in the 17 patients studied 2 or more years after transplantation, 12 (71%) had intimal thickening. There were no complications, including vessel spasm, thrombosis, or perforation with the Doppler guide wire or the IVUS catheter.

Hemodynamic Data
There was no change in the heart rate or mean arterial blood pressure during adenosine hyperemia or in the mean heart rate during nitroglycerin hyperemia. The mean arterial blood pressure significantly decreased during nitroglycerin hyperemia compared with baseline (94.0±11.9 versus 105.8±10.0 mm Hg, respectively, P<.05) (Table 2Down).


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  		Table 2. Effects of Intracoronary Adenosine and Nitroglycerin on Hemodynamics, Coronary Flow Velocity, CSA, and Volumetric CBF in Orthotopic Heart Transplant Recipients

Coronary Flow Velocity Responses
Both adenosine and nitroglycerin increased APV (cm/s) compared with baseline (from 18.9±4.9 to 56.0±11.5 cm/s for adenosine and from 20.2±5.3 to 49.1±11.5 cm/s for nitroglycerin; both P<.05) (Table 2Up, Fig 3Down). The percent change from baseline in APV was significantly greater for adenosine compared with nitroglycerin (209±65% versus 153±72%, respectively; P<.01) (Table 2Up). Similarly, the coronary flow velocity reserve was significantly higher for adenosine compared with nitroglycerin (3.1±0.6 versus 2.5±0.7, respectively; P<.001) (Fig 4Down).



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  		Figure 3. Bar graphs show baseline values and hyperemic responses after administration of 12 to 18 µg IC adenosine and 150 to 200 µg IC nitroglycerin. A, Average peak velocity (APV, cm/s). Adenosine hyperemia resulted in a 210% increase in APV, which was significantly higher than the 150% increase recorded during nitroglycerin hyperemia. B, Epicardial luminal CSA (mm2). There was no increase in luminal CSA during adenosine hyperemia. However, there was a 6% increase in CSA recorded during nitroglycerin hyperemia. C, Volumetric CBF (mL/min). Adenosine hyperemia resulted in a 200% increase in CBF, which was not significantly higher than the 170% increase recorded during nitroglycerin hyperemia. {blacksquare} indicates baseline; {square}, hyperemia. *P<.05 hyperemia vs baseline.



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  		Figure 4. Bar graphs show that A, Coronary flow velocity reserve (CFVR), defined as the quotient of the hyperemic to baseline coronary flow velocity, was significantly higher for adenosine compared with nitroglycerin and B, Volumetric CBF reserve (CBFR), defined as the quotient of the hyperemic to baseline CBF, was similar for both adenosine and nitroglycerin. *P<.01 adenosine vs nitroglycerin.

Luminal CSA Responses
Epicardial lumen CSA was similar during maximal adenosine hyperemia compared with baseline (17.4±3.8 versus 17.3±4.0 mm2, respectively; P=NS) but was significantly greater during nitroglycerin hyperemia compared with baseline (18.7±3.8 versus 17.3±4.0 mm2, 6.2±3.6% change; P<.05) (Table 2Up, Fig 3Up).

Volumetric CBF Responses
Baseline volumetric CBF was similar with adenosine and nitroglycerin before drug administration (100±36 and 102±38 mL/min, respectively; P=NS) (Table 2Up). Hyperemic CBF responses were also similar during adenosine and nitroglycerin hyperemia (297±99 and 276±87 mL/min, respectively; P=NS) (Table 2Up, Fig 3Up). There was no difference in the CBF reserve for adenosine and nitroglycerin (3.0±0.7 and 2.7±0.7 respectively; P=NS) (Fig 4Up).

Effects of Intimal Thickening
There were no differences in the resting APV and luminal CSA or hyperemic APV and luminal CSA responses during either adenosine or nitroglycerin administration in patients with and without intimal thickening (Table 3Down). The percent change in hyperemic APV was also unaffected by the presence or absence of intimal thickening (229±59% versus 195±72%, respectively, for adenosine; 178±78% versus 137±68%, respectively, for nitroglycerin; both P=NS) (Table 3Down). Similarly, the percent change in CSA during maximal hyperemia was unaffected by the presence or absence of intimal thickening (1±2% versus 0±2%, respectively, for adenosine; 7±3% versus 6±4%, respectively, for nitroglycerin; both P=NS) (Table 3Down).


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  		Table 3. Effects of Intimal Thickening on Resting and Hyperemic APV and Epicardial CSA

Resting CBF was similar in patients with and without intimal thickening (Table 4Down). The presence of intimal thickening did not impair the CBF reserve during adenosine and nitroglycerin hyperemias. For adenosine, the CBF reserve was similar in the presence and absence of intimal thickening (3.1±0.6 and 2.9±0.7, respectively; P=NS) (Table 4Down). For nitroglycerin, CBF reserve was paradoxically higher in patients with intimal thickening compared with patients without intimal thickening (3.2±0.6 versus 2.5±0.6, respectively, P<.05) (Table 4Down).


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  		Table 4. Effects of Adenosine and Nitroglycerin on Volumetric CBF Stratified by Intimal Thickening and Time After Transplantation

Comparisons of the CBF reserve between adenosine and nitroglycerin were similar when stratified by the presence or absence of intimal thickening. In patients with intimal thickening, the CBF reserve was 3.1±0.6 for adenosine and 3.2±0.6 for nitroglycerin (P=NS) (Table 4Up). There was also no difference between the adenosine and nitroglycerin CBF reserve in patients without intimal thickening (Table 4Up).

Effects of Transplantation Duration
Baseline CBF before nitroglycerin administration was significantly higher in patients 1 month after transplantation compared with patients 2 or more years after transplantation (130±26 versus 83±34 mL/min; P<.05) (Table 4Up). Baseline CBF before adenosine administration in patients 1 month after transplantation compared with patients 2 or more years after transplantation was not statistically different (131±46 versus 90±34 mL/min, P=NS) (Table 4Up).

CBF reserve was similar in early compared with late transplant recipients. The CBF reserve for adenosine was 2.6±0.9 in patients 1 month after transplantation compared with 3.0±0.5 in patients 2 or more years after transplantation (P=NS). Similarly, the CBF reserve for nitroglycerin was 2.6±0.4 in patients 1 month after transplantation compared with 2.9±0.8 in patients 2 or more years after transplantation (P=NS) (Table 4Up).

There were no differences in the CBF reserve between adenosine and nitroglycerin when stratified by time after transplantation. In patients 1 month after transplantation, the CBF reserve was 2.6±0.9 for adenosine and 2.6±0.4 for nitroglycerin (P=NS) (Table 4Up). Similarly, there were no differences between the adenosine and nitroglycerin CBF reserve in patients 1 year and 2 or more years after transplantation (Table 4Up).


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
This study examined epicardial luminal CSA and resistance vessel responses after endothelium-independent vasodilator administration. Intimal thickening did not affect coronary conduit vessel responses after endothelium-independent vasodilator administration in angiographically normal heart transplant recipients. This study also demonstrated that intimal thickening, when present in the epicardial conduit vessels, did not correlate with impaired resistance vessel responses. Furthermore, the data showed that adenosine significantly decreased microvascular resistance with no effect on maximal hyperemic luminal CSA, while nitroglycerin decreased microvascular resistance and increased luminal CSA. Therefore, although adenosine hyperemia resulted in a significantly higher APV and coronary flow velocity reserve compared with nitroglycerin, the duality of the nitroglycerin vasodilator response on both epicardial conduit and microvascular resistance vessels resulted in similar increases in volumetric CBF and similar CBF reserves. This study is one of the first reports in patients in which sequential Doppler guide wire and IVUS techniques were used to calculate CBF.

Differential Effects of Adenosine and Nitroglycerin on Coronary Artery Reactivity
Nitroglycerin is a clinically important endothelium-independent vasodilator that increases epicardial luminal CSA approximately 20% as measured by quantitative angiography after a single 0.4-mg sublingual dose.10 23 24 In this study, luminal CSA was measured at 15 seconds after administration of both adenosine and nitroglycerin, which corresponded to the approximate time of maximal hyperemia for both drugs. The 6% change in CSA during peak nitroglycerin hyperemia is substantially less than the 24% seen at 4.5 minutes after a 0.4-mg dose of sublingual nitroglycerin in a previous study of heart transplant recipients.9 The difference between study results likely reflects the time after drug administration that the changes in CSA were measured, with greater vasodilation occurring more than 1 minute after nitroglycerin hyperemia has abated.

In contrast to nitroglycerin, adenosine produces a profound coronary microvascular dilatory response,25 26 27 28 which is mediated by specific purinergic (A2) receptors on the cell membrane of the resistance vessel smooth muscle cell.29 30 In humans, a bolus of intracoronary adenosine produces maximal flow velocity hyperemia within 15 seconds after administration that persists for less than 15 seconds.26 In this study, adenosine had no vasodilating effect on epicardial conduit vessels, confirming the primary vasodilatory effect of adenosine on resistance vessels. Similar data have been reported in animal experiments using simultaneous 2D intravascular Doppler and ultrasound imaging after bolus infusion of intracoronary adenosine.31

Conflicting data from two studies of heart transplant recipients with no angiographically apparent arteriopathy show an increase in the mean diameter of the LAD artery of 8% after bolus intracoronary adenosine12 and 15% during continuous intracoronary adenosine infusion.13 The study using bolus intracoronary adenosine supports a direct vasodilatory effect of adenosine on conduit vessels.12 In that study of 9 heart transplant patients,12 gated IVUS images at an unspecified time after adenosine administration were used to measure the vasodilatory response, which was unrelated to peak hyperemia. In the study that used continuous intracoronary adenosine infusion,13 the increase in vessel diameter measured by quantitative angiography may have been a result of flow-mediated vasodilation.

Increased CBF, independent of pharmacological stimuli, may result in flow-mediated epicardial coronary artery dilation.32 33 34 35 36 In the current study, by design, the proximal infusion of the two vasodilators precluded separating the mechanism of conduit vessel vasodilation. Therefore, the component of increase in CSA recorded after nitroglycerin administration attributable to flow-mediated vasodilation is unknown. Conversely, flow-mediated vasodilation after adenosine, if present, may have lagged behind the time to peak hyperemia. A time-dependent mechanism of flow-mediated vasodilation is suggested in one animal study in which flow-dependent dilation did not occur until 1 minute after changes in blood flow were recorded.35

Intimal Thickening By IVUS: Transplant Arteriopathy?
High-frequency IVUS imaging demonstrates a characteristic three-layered appearance in nondiseased peripheral muscular arteries.37 38 In contrast, discriminant analysis of 30-MHz IVUS images from the coronary arteries of explanted hearts showed that at least 178 µm of measurable intimal thickening is required before a three-layered appearance is visualized.22 The degree of intimal thickening is age related.22 39 40 41 In an IVUS study of intact hearts at autopsy from patients with no clinical history of coronary artery disease, the mean age of patients with nonlayered and three-layered ultrasound images was 27.1 and 42.8 years, respectively.22 Of the 14 patients in the present study with no IVUS evidence of intimal thickening, only 1 had a donor heart >=40 years old.

Two studies have shown that epicardial intimal thickening detected by IVUS imaging that is angiographically inapparent appears in the majority of patients after heart transplantation.9 10 However, conflicting data11 show that at 1 year after transplantation, only 3 of 11 patients with 6 of 30 coronary segments (20%) studied had intimal thickening. The difference between the two studies is not readily apparent, since both used the same ultrasound system, had similar definitions of intimal thickening, and interrogated multiple segments within the study vessel. Since the incidence and severity of intimal thickening by IVUS imaging and histological examination increase with time after transplantation,11 42 patient selection may have contributed to the discrepancies. Furthermore, differences in the age of the donor hearts may also have contributed to the study differences. In the present study, approximately 70% of patients studied 2 or more years after transplantation had intimal thickening at the site of ultrasound imaging in the study vessel.

The functional significance of intimal thickening has been evaluated previously. No significant correlation was observed between the amount of intimal thickening or time after transplantation and the degree of epicardial vasodilation after administration of sublingual nitroglycerin.10 Although endothelium-dependent vasoreactivity is abnormal after acetylcholine administration in transplant recipients,11 12 13 14 15 16 when vasomotor responses were stratified by the presence or absence of intimal thickening, 9 of 11 vessel segments with intimal thickening studied in patients more than 5 years after transplantation had preserved endothelium-dependent vasodilation.11

In the present study, although endothelial function was untested with acetylcholine or substance P, the presence of intimal thickening did not diminish either conductance or resistance vessel responses after adenosine or nitroglycerin administration. Resting and hyperemic APV, CSA, volumetric CBF, as well as coronary flow velocity and blood flow reserves were all similar in the presence and absence of intimal thickening, suggesting preserved conduit and resistance vessel reactivity. One might speculate that these data, in conjunction with the natural history studies showing that coronary intimal thickening is an age-related process, suggest that angiographically inapparent intimal thickening is of minimal clinical relevance.

Study Limitations
IVUS
Acquisition of the IVUS images was not gated to the cardiac cycle. Therefore, measurement of baseline and hyperemic CSA does not account for conformational changes in the vessel throughout the cardiac cycle. Averaging four frames to obtain mean CSA for each study condition was designed to minimize any significant effect due to systolic and diastolic changes in vessel area. The absence of a vasodilating effect after bolus intracoronary adenosine because a gated image-area-averaging technique was not used is unlikely to be a result of the method. In one animal study, no increase in conduit vessel diameter was seen, after bolus intracoronary adenosine, using an intravascular imaging system gated to the cardiac cycle.31

The findings in this study are based on examination of only a limited area within the proximal or midportion of each study vessel. However, transplant arteriopathy is a diffuse, supposedly heterogeneous disease process that is angiographically characterized by concentric epicardial narrowing with pruning of the distal vasculature.6 Since intimal thickening is often a patchy process that becomes more diffuse with increasing time after transplantation,8 42 43 some patients assigned to the group without intimal thickening may in fact have had disease at another location in the study vessel.

Sequential Intravascular Doppler and Ultrasound Imaging
Doppler flow velocity and IVUS measurements were performed sequentially, not simultaneously. Sequential acquisition of the data, while susceptible to minor fluctuations in systemic hemodynamics, allowed for accurate measurements to be obtained at nearly the same reference point within the study vessel. With a study protocol designed for simultaneous data acquisition, accurate measurement of flow velocity may be reduced by a flattening of the velocity profile due to vessel lumen obstruction by the ultrasound imaging catheter and a velocity sample volume distal to the cross-sectional imaging plane area.44 Additionally, as currently configured, the IVUS and Doppler flow velocity systems create radiofrequency interference when used simultaneously, which results in a radial-spoke pattern on the IVUS image, that can degrade the image quality.

Pharmacological Considerations
Although the order of adenosine and nitroglycerin administration was not randomized, the short (<45 seconds) effect and complete metabolism of adenosine has no influence on nitroglycerin responses. Since the hemodynamic effects of nitroglycerin could potentially influence adenosine responses, the order of drug administration was not randomized.

Clinical Implications
The alterations in CBF identified in this study represent an integration of conduit and resistance vessel reactivity. In orthotopic heart transplant recipients, epicardial luminal intimal thickening does not diminish CBF responses after pharmacological challenge with endothelium-independent vasodilators. Therefore, intimal thickening does not appear to be a significant marker for abnormal conduit and resistance vessel vasoreactivity.


*    Selected Abbreviations and Acronyms
 
APV = average peak velocity
CBF = coronary blood flow
CSA = cross-sectional area
2D = two-dimensional
IVUS = intravascular ultrasound
LAD = left anterior descending


*    Acknowledgments
 
The authors wish to thank the J.G. Mudd Cardiac Catheterization Laboratory team and Denise Fehl for manuscript preparation.


*    Footnotes
 
Reprint requests to Morton J. Kern, MD, Professor of Medicine, Director, J.G. Mudd Catheterization Laboratory, St Louis University Hospital, 3635 Vista Ave at Grand Blvd, St Louis, MO 63110.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
up arrowDiscussion
*References
 

  1. Miller LW. Long term complications of heart transplantation. Prog Cardiovasc Dis. 1991;33:229-282. [Medline] [Order article via Infotrieve]
  2. Gao SZ, Schroeder JS, Alderman EL, Hunt SA, Silverman JF, Wiederhold V, Stinson EB. Clinical and laboratory correlates of accelerated coronary artery disease in the cardiac transplant patient. Circulation. 1987;76(suppl V):V-56-V-61.
  3. Hunt SA. Complications of heart transplantation. J Heart Transplant. 1983;3:70-74.
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