Determinants of coronary remodeling in transplant coronary disease: a simultaneous intravascular ultrasound and Doppler flow study.

BACKGROUND: Coronary remodeling plays a significant role in lumen loss in transplant allograft vasculopathy (TxCAD), but the determinants of remodeling are unknown. We assessed the relationship between remodeling and plaque topography, coronary compliance, and blood flow in TxCAD. METHODS AND RESULTS: One artery in each of 27 transplant patients was investigated with simultaneous intravascular ultrasound and coronary flow measurements (basal and hyperemic by Doppler flow wire). At 4 to 8 different cross sections (mean 5.1+/-1. 2), plaque topography (concentric or eccentric) was determined, and total vessel area, lumen area, and intimal/medial area (IMA) were measured. Mean remodeling ratio (vessel area/IMA) in eccentric lesions (E, n=28) was significantly larger than that in concentric lesions (C, n=70) (E 5.87+/-0.93 versus C 3.58+/-0.62; P<0.001), despite similar IMA (E 3.89+/-0.68 versus C 3.90+/-0.41; P=NS) and distribution of imaged segments. Remodeling ratio was consistently larger in eccentric lesions in all 3 vessel segments when analyzed separately, and mean remodeling ratio for each artery was larger in vessels with predominantly eccentric lesions. Coronary compliance ([Delta lumen area/diastolic lumen area]/Delta mean arterial pressure x 10(3)) was also significantly greater in eccentric lesions versus concentric lesions (proximal 1.00+/-0.39 versus 0.22+/-0.04; mid 0.71+/-0.17 versus 0.21+/-0.10; distal 0.43+/-0.13 versus 0. 01+/-0.08; all P<0.01). Coronary flow reserve was also significantly higher in coronary arteries with primarily eccentric lesions (E 2. 49+/-0.64 versus C 1.87+/-0.28; P<0.01). CONCLUSIONS: Vessel remodeling in transplant vasculopathy is significantly greater in eccentric lesions than in concentric lesions, possibly due to greater coronary compliance and resistive vessel function.

Local L-arginine delivery after balloon angioplasty reduces monocyte binding and induces apoptosis.

BACKGROUND: Local administration of L-arginine after balloon angioplasty has been shown to enhance NO generation and inhibit lesion formation. In this study, we assessed the mechanisms by which local delivery of L-arginine inhibits lesion formation. METHODS AND RESULTS: New Zealand White rabbits (n=56) were fed a 1% cholesterol diet. After 1 week, both iliac arteries were balloon-denuded, and a local drug delivery catheter was introduced into both iliac arteries to deliver either L-arginine (800 mg/5 mL with and without 100 microCi L-[2,3-(3)H]-arginine) or saline. Monocyte-endothelial interaction was assessed by functional binding assay; NO activity was measured by chemiluminescence. Intramural administration of radioactively labeled L-arginine led to significantly higher counts in comparison to the contralateral segment for up to 1 week after delivery (676+/-223 versus 453+/-93 cpm/mg; P<0.02); this was associated with significantly higher NO levels in the L-arginine-treated segments (394.4+/-141.6 versus 86.3+/-34.3 nmol/mg; P<0.01). Even after 2 to 3 weeks, monocyte binding was significantly decreased by treatment with L-arginine as compared with saline infusion (P<0.01). After 4 weeks, there was a 9-fold greater number of apoptotic cells in the vessel wall of L-arginine as compared with the saline-treated segments (P<0.05). CONCLUSIONS: Intramural delivery of L-arginine immediately after angioplasty causes a sustained increase in tissue L-arginine levels associated with enhancement of local NO synthesis. The local increase in NO synthesis is associated with an attenuation of monocyte binding and increased apoptosis of resident macrophages. This treatment strategy could be valuable for the prevention and management of restenosis.

Reduction of aortic wall motion inhibits hypertension-mediated experimental atherosclerosis.

Hypertension is a well-known risk factor for coronary artery disease and carotid and lower extremity occlusive disease. Surgically induced hypertension in hypercholesterolemic animals results in increased aortic wall motion and increased plaque formation. We tested the hypothesis that reduction in aortic wall motion, despite continued hypertension, could reduce plaque formation. New Zealand White rabbits (n=26) underwent thoracic aortic banding to induce hypertension and were fed an atherogenic diet for 3 weeks. In 13 rabbits, a segment of aorta proximal to an aortic band was externally wrapped to reduce wall motion. All animals were fed an atherogenic diet for 3 weeks. Four groups were studied: 1, coarctation control (no wrap, n=7); 2, coarctation with loose wrap (n=6); 3, coarctation with firm wrap (n=7); and 4, control (noncoarcted, n=6). Wall motion, blood pressure, and pulse pressure were measured at standard reference sites proximal and distal to the coarctation by use of intravascular ultrasound. Quantitative morphometry was used to measure intimal plaque. Mean arterial pressure and cyclic aortic wall motion were equally increased proximal to the aortic coarctation in all 3 coarcted rabbit groups compared with the control group (P:<0.001). Wall motion in the segment of aorta under the loose and firm wraps was no different from the control value. The external wrap significantly reduced intimal thickening in the 4 groups by the following amounts: group 1, 0.30+/-0.03 mm(2); group 2, 0.06+/-0.02 mm(2); group 3, 0. 04+/-0.02 mm(2); and group 4, 0.01+/-0.01 mm(2) (P:<0.001). Localized inhibition of aortic wall motion in the lesion-prone hypertensive aorta resulted in significant reduction in intimal plaque formation. These data suggest that arterial wall cyclic motion may stimulate cellular proliferation and lipid uptake in experimental atherosclerosis.

Vascular endothelial growth factor synthesis in vascular smooth muscle cells is enhanced by 7-ketocholesterol and lysophosphatidylcholine independently of their effect on nitric oxide generation.

Nitric oxide (NO) generated by inducible NO synthase (iNOS) enhances vascular endothelial growth factor (VEGF) synthesis in vascular smooth muscle cells (VSMC) and both NO and modified low density lipoprotein (LDL) augment VEGF production in macrophages. Oxidized LDL (oxLDL) are known inhibitors of NO generation in the cells of vascular wall. As the relationship between VEGF, iNOS and oxLDL has not been well elucidated, we studied the effect of two main components of oxLDL, 7-ketocholesterol (7-Kchol) and lysophosphatidylcholine (LPC), on VEGF and NO synthesis in rat VSMC and on VEGF synthesis in human VSMC. Both LPC and 7-Kchol significantly augmented VEGF production in rat and human VSMC. Increase in VEGF generation was related to the activation of VEGF promoter by both 7-Kchol and LPC and enhancement of VEGF mRNA transcription. In rat, VSMC IL-1beta-induced NO generation and enhanced VEGF synthesis. 7-Kchol decreased rat iNOS promoter activity, iNOS expression and NO generation, but it did not impair IL-1beta-induced VEGF synthesis. LPC did not significantly influence IL-1beta-induced NO production in rat VSMC and VEGF synthesis was significantly enhanced by combined treatment with IL-1beta and LPC in comparison to the effect of either compound alone. The results indicate that VEGF and NO synthesis in VSMC can be modulated by oxLDL. Those interactions might have an effect on the plaque growth and might be of relevance for the physiology of vascular wall cells.

Impact of curve distortion errors on intravascular ultrasound measurements and three-dimensional reconstructions.

Intravascular ultrasound distortion errors and longitudinal reconstructions are primarily determined by the angle of curvature. The error in commonly encountered angles is relatively small.

Plasma levels of cardiac troponin I after prolonged strenuous endurance exercise.

This study provides biochemical evidence that ultraendurance exercise may cause subclinical myocardial damage, even in well-trained cyclists. The cellular nature of this damage and its clinical relevance remain unknown at present.

Acute myocardial infarction and vascular remodeling.

We used intravascular ultrasound to show that outward remodeling predominates in lesions responsible for acute myocardial infarction, whereas negative remodeling is far more prevalent in lesions responsible for chronic stable angina. The total cholesterol:high-density lipoprotein ratio was also strongly correlated with outward remodeling.

Clinical use of intravascular ultrasound.

Intravascular ultrasound has dramatically changed our view of atherosclerotic disease and has helped to define mechanisms of therapeutic interventions, providing a new rationale for selection of appropriate devices. Currently, this technology is used for sizing and orientation of commonly performed interventions such as balloon angioplasty and directional atherectomy. The information from intravascular ultrasound has also led to a dramatic change in the deployment algorithm of stents. Further improvements in catheter design and the findings from clinical trials utilizing intravascular ultrasound will help define a practical role for this new technology.

Vessel tearing at the edge of intracoronary stents detected with intravascular ultrasound imaging.

Stent deployment strategies have changed significantly in the past 2 yr, with "high-pressure" balloon inflations postdilatation being performed in the large majority of cases. There is currently little information about the effects of high pressure on the geometry of stent expansion and on the adjacent areas of the vessel wall. Intravascular ultrasound (IVUS) imaging is well-suited to investigate these issues, since it provides information not only about stent expansion and apposition but also about adjacent vessel-wall morphology at transition points such as the articulation site of the stent and the the stent borders. We report on the results of a cohort of 30 consecutive stent cases which were systematically examined by IVUS following high-pressure inflation. All deployments were deemed successful by angiographic inspection. However, in 6 cases, intimal disruptions or "edge tears" were noted at the stent borders by IVUS. In 5 cases, edge tears were seen to occur at the distal border, whereas in one case edge tears were seen at both the proximal and distal edges of the stent. No angiographic and sonographic parameters were different except percent plaque area at the stent margins, which was significantly higher (53 +/- 11%) in the lesions with edge tears, compared to 40 +/- 10% plaque area in the group without evidence of pocket flaps (P = 0.007). This experience suggests that intimal disruptions or "edge tears" are a relatively common occurrence following high-pressure stent deployment, and may be related to the extent of marginal dissections.

Effects of stenting on adjacent vascular distensibility and neointima formation: role of nitric oxide.

Intravascular stents increase long-term patency but their effects on the vascular mechanics of adjacent segments have not been studied. In this study, stents were deployed in the rabbit abdominal aorta after 1 week of normal diet, 1% cholesterol diet or 1% cholesterol diet with L-nitro arginine (L-NA 60 mg/l water). Intravascular ultrasound showed a small distal decrease in vessel distensibility (area/pressure * 100) before stenting. Distensibility was almost abolished by stenting (0.12 +/- 0.01, p < 0.001), but was increased proximal to the stent and decreased distal to the stent both acutely (proximal: 1.18 +/- 0.10 vs distal: 0.65 +/- 0.06, p < 0.001), and at 4 weeks (proximal: 1.05 +/- 0.08 vs distal: 0.37 +/- 0.07, p < 0.001). Nitric oxide (NO) activity was enhanced proximal to and within the stent, and remained constant distal to the stent, (versus control, proximal: 57 +/- 23%, stent: 136 +/- 35%, distal: 2 +/- 12%, p < 0.01). The I/M ratio was significantly higher proximal to and within the stent than in the distal segment (proximal: 0.40 +/- 0.10, stent: 0.37 +/- 0.12, distal: 0.12 +/- 0.11, p < 0.01). NO blockade with L-NA prevented hyperdistensibility proximally, and significantly increased the I/M ratio within the stent and distally (stent: 0.81 +/- 0.19, distal: 0.30 +/- 0.10, p < 0.05) but not proximally (0.38 +/- 0.09). In conclusion, aortic stenting increases proximal vascular distensibility and intimal lesion formation. Nitric oxide blockade augments intimal growth within but not proximal to the stent.

Predictors and outcomes of stent thrombosis: an intravascular ultrasound registry.

AIMS: To investigate whether intravascular ultrasound provides additional information regarding the prediction of stent thrombosis, a retrospective multicentre registry was designed to enrol patients with stent thrombosis following stent deployment under ultrasound guidance. METHODS AND RESULTS: A total of 53 patients were enrolled (mean age 61+/-9 years) with stable angina (43%), unstable angina (36%), and post-infarct angina (21%) who underwent intracoronary stenting. The majority had balloon angioplasty alone prior to stenting (94%) with 6% also undergoing rotational atherectomy. The indication for stenting was elective (53%), suboptimal result (32%) and bailout (15%). There were 1.6+/-0.8 stents/artery with 87% undergoing high-pressure dilatation (> or =14 atmospheres). The minimum stent area was 7.7+/-2.8 mm(2)with a mean stent expansion of 81.5+/-21.9%. Overall, 94% of cases demonstrated one abnormal ultrasound finding (stent under-expansion, malapposition, inflow/outflow disease, dissection, or thrombus). Angiography demonstrated an abnormality in only 32% of cases (chi-square=30.0, P<0.001). Stent thrombosis occurred at 132+/-125 h after deployment. Myocardial infarction occurred in 67% and there was an overall mortality of 15%. CONCLUSION: On comparison with angiography, the vast majority of stents associated with subsequent thrombosis have at least one abnormal feature by intravascular ultrasound at the time of stent deployment.

Local intramural delivery of L-arginine enhances nitric oxide generation and inhibits lesion formation after balloon angioplasty.

BACKGROUND: Long-term oral administration of L-arginine has been shown to enhance production of nitric oxide (NO) and to reduce lesion formation. The goal of this study was to determine whether local intramural administration of L-arginine could enhance NO generation and reduce intimal thickening. METHODS AND RESULTS: New Zealand White rabbits (n = 27) received a 1% cholesterol diet. For the short-term study, after 1 week of diet, both iliac arteries were balloon injured. Four weeks later, vasoreactivity was assessed angiographically during infusion of acetylcholine (Ach) before and after delivery of L-arginine or saline into the right or left iliac artery (800 mg/5 mL; 0.2 mL/min, 15 minutes) by use of a local drug-delivery balloon. Vessels were then harvested for measurements of NO. For the long-term study, after balloon injury, drugs were delivered as above into the iliac arteries. Two and 4 weeks after L-arginine delivery, vasoreactivity was determined. Subsequently, the iliac arteries were harvested for histomorphometric analysis and measurements of NO. In the short-term study, local delivery of L-arginine restored endothelium-dependent vasodilatation (Ach 10(-5) mol/L; L-arginine +35 +/- 10%; saline -14 +/- 5%; P < .001) and enhanced local production of nitrogen oxides (L-arginine 152 +/- 28; saline 78 +/- 12 nmol/L per milligram of tissue per hour; P < .04). In the long-term study, local administration of L-arginine enhanced vascular NO production as long as 1 week after the injury (L-arginine 394.4 +/- 141.6; saline 86.3 +/- 34.3 nmol/L per milligram of tissue per hour; P < .01) and reduced intimal thickening 4 weeks later (intima/ media ratio: L-arginine 0.56 +/- 0.1; saline 1.40 +/- 0.2; P < .001), largely due to suppression of macrophage accumulation. CONCLUSIONS: A single intramural administration of L-arginine enhances vascular NO generation and inhibits lesion formation. Local augmentation of NO production at the site of balloon angioplasty may be a novel strategy to prevent restenosis.

Enhancement of spatial orientation of intravascular ultrasound images with side holes in guiding catheters.

BACKGROUND: Intravascular ultrasound (IVUS) images are typically viewed and recorded in an arbitrary rotational orientation. This study was performed to validate a new method for improved orientation of sonographic vascular cross-sections. METHODS AND RESULTS: We have tested a simple technique for rotational indexing of IVUS in cases in which guiding catheters with side holes are used. Although guiding catheters are opaque to ultrasonography, the side holes transmit the beam and therefore can be easily identified. The orientation of the side holes, which is characteristic for each make of guiding catheter, can be used to determine the anatomically appropriate rotational orientation of the IVUS image. In this study images of four commercially available side-hole guiding catheters were viewed in vitro to confirm the visibility of the side holes and to characterize their orientation for purposes of rotational orientation of images. Feasibility tests of rotational orientation based on side holes were then performed in canine coronary arteries (n = 3) and in six human coronary arteries. Three serial imaging runs in each clinical case yielded a mean variability in rotational orientation of 7.5 +/- 1.5 degrees. CONCLUSION: Validation testing of the side-hole technique demonstrates the potential for consistent and anatomically appropriate orientation of intravascular ultrasound images.

Regression of atherosclerosis: role of nitric oxide and apoptosis.

BACKGROUND: We have recently found that administration of L-arginine to hypercholesterolemic rabbits induces regression of preexisting lesions. Others have previously shown that activation of the L-arginine/nitric oxide (NO) synthase pathway can induce apoptosis of vascular cells in vitro. Accordingly, the current study was designed to determine if dietary supplementation of L-arginine induces apoptosis of intimal lesions and if this effect is mediated through the NO synthase pathway. METHODS AND RESULTS: Male New Zealand White rabbits were fed a 0.5% cholesterol diet for 10 weeks and subsequently placed on 2.5% L-arginine HCl in the drinking water, and the cholesterol diet was continued for 2 weeks, at which time the aortas were harvested for histological studies. L-Arginine treatment increased the number of apoptotic cells (largely macrophages) in the intimal lesions by 3-fold (11.9+/-3.9 vs 3.9+/-1. 4 apoptotic cells/mm2, P<0.01). In subsequent studies, aortas were harvested for ex vivo studies. Aortic segments were incubated in cell culture medium for 4 to 24 hours with modulators of the NO synthase pathway. The tissues were then collected for histological studies and the conditioned medium collected for measurement of nitrogen oxides by chemiluminescence. Addition of sodium nitroprusside (10(-5) mol/L) to the medium caused a time-dependent increase in apoptosis of vascular cells (largely macrophages) in the intimal lesion. L-Arginine (10(-3) mol/L) had an identical effect on apoptosis, which was associated with an increase in nitrogen oxides released into the medium. These effects were not mimicked by D-arginine, and they were antagonized by the NO synthase inhibitor L-nitro-arginine (10(-4) mol/L). The effect of L-arginine was not influenced by an antagonist of cGMP-dependent protein kinase, nor was the effect mimicked by the agonist of protein kinase G or 8-BR cGMP. CONCLUSIONS: These results indicate that supplemental L-arginine induces apoptosis of macrophages in intimal lesions by its metabolism to NO, which acts through a cGMP-independent pathway. These studies are consistent with our previous observation that supplementation of dietary arginine induces regression of atheroma in this animal model. These studies provide a rationale for further investigation of the therapeutic potential of manipulating the NO synthase pathway in atherosclerosis.

Antioxidant diet preserves endothelium-dependent vasodilatation in resistance arteries of hypercholesterolemic rabbits exposed to environmental tobacco smoke.

Environmental tobacco smoke (ETS) has been shown to impair endothelium-dependent vasodilation in vitro. This study was performed to investigate the effect of ETS on acetylcholine (ACh)-mediated blood pressure changes in vivo. Seventeen New Zealand White rabbits were fed a cholesterol diet (0.3%) for 13 weeks. Ten animals were exposed to ETS for 6 h/day, and seven animals were not exposed to ETS (non-ETS). Four of the ETS and three of the non-ETS-exposed rabbits received an antioxidant vitamin diet before and during their cholesterol diet for 21 weeks. Six rabbits served as healthy controls. To determine endothelium-dependent and independent blood pressure (BP) responses, BP was measured through a Tygon catheter, inserted into the right carotid artery at baseline and after each of three incremental intravenous doses of norepinephrine (NE; 1, 4, and 20 microg/kg), ACh (3.3, 10, and 30 microg/kg), and nitroglycerin (NTG; 1, 10, and 40 microg/kg). After NE, BP increases were significantly attenuated in the ETS group (p = 0.001) but not in animals receiving the antioxidant supplement. At both the middle and high ACh concentrations, ETS (p = 0.03 and p = 0.01, respectively) and hypercholesterolemia (p = 0.03 and p = 0.06, respectively) attenuated ACh-induced reductions in BP. At the highest ACh concentration, vitamins enhanced the reduction in BP (p = 0.002) and blocked the effect of ETS (p = 0.04). Neither ETS nor vitamins influenced NTG-induced decreases in BP. A combined antioxidant-vitamin diet can preserve endothelium-dependent vasodilatation in the hypercholesterolemic rabbit exposed to ETS.