Functional and morphological findings in heart transplant recipients with a normal coronary angiogram: an analysis by dobutamine stress echocardiography, intracoronary Doppler and intravascular ultrasound.

BACKGROUND: Coronary angiography is still the routine screening method for cardiac allograft vasculopathy in most transplant centers. This study was designed to analyze functional and morphologic changes in heart transplant recipients with normal angiographic findings. METHODS: Dobutamine stress echocardiography and intracoronary ultrasound were obtained in 56 patients with a normal coronary angiogram 41+/-31 months after heart transplantation. Intracoronary Doppler flow velocity measurements before and after intracoronary adenosine administration were performed in 34 of 56 patients. Any regional wall motion abnormalities detected by stress echocardiography were regarded as abnormal. By quantitative intracoronary ultrasound analysis using a 6-grade scale, a mean grade of all coronary segments >3.0 was defined as significant intimal hyperplasia. RESULTS: Only 17 patients (30%) showed both a normal dobutamine stress echocardiogram and absence of significant intimal hyperplasia by intravascularultrasound. Abnormal findings were observed in 39 patients (70%): both by dobutamine stress echocardiography and intravascular ultrasound in 22 patients, by intravascular ultrasound alone in 11 patients, and by dobutamine stress echocardiography alone in 6 patients. Coronary flow velocity reserve did not discriminate between patients with normal or abnormal intravascular ultrasound or dobutamine stress echocardiographic findings. Conclusions: Only a minority of heart transplant patients with a normal coronary angiogram is free of pathological changes, when assessed by intravascular ultrasound and dobutamine stress echocardiography. Coronary flow velocity reserve does not seem useful to further characterize these patients.     

Changes in coronary endothelial function predict progression of allograft vasculopathy after heart transplantation.

OBJECTIVE: Coronary endothelial dysfunction may be an early marker for cardiac allograft vasculopathy (CAV) in orthotopic heart transplant recipients. We used serial studies to evaluate changes in coronary endothelial function in patients with and without clinically evident CAV. BACKGROUND: In serial studies with intravascular ultrasound (IVUS) and Doppler flow wire measurements, we previously demonstrated that annual decrements in coronary endothelial function are associated with progressive intimal thickening. METHODS: We studied 45 patients annually, beginning at transplantation until pre-specified end-points (angiographic CAV or cardiac death) were reached. At each study, we measured coronary endothelial function using intracoronary infusions of adenosine, acetylcholine, and nitroglycerin. We simultaneously recorded IVUS images and Doppler velocities. RESULTS: Of the 45 patients studied, 9 reached end-points during the study (6 had CAV and 3 died). The mean annual change in area response to acetylcholine was -4.5% +/- 3.0% in patients who reached end-points and -0.9% +/- 1.5% in those who did not (p = 0.04). The mean annual decrement in flow response to acetylcholine was greater in patients who reached end-points (-31% +/- 11% vs -5% +/- 5%, p = 0.08). Responses to adenosine and nitroglycerin did not differ. CONCLUSIONS: When serial responses were evaluated, patients with end-points had more rapid decreases in endothelial function. The rate of disease progression may be more important than the absolute degree of intimal thickening in early CAV. These data implicate endothelial dysfunction in the development of clinically significant vasculopathy and suggest that serial studies of endothelial function may provide important prognostic information about the development of CAV after heart transplantation.     

Coronary endothelial dysfunction as a predictor of intimal thickening in the long term after heart transplantation.

OBJECTIVES: The mechanisms of cardiac allograft vasculopathy and its predisposing factors are multifactorial and as yet not well established. To determine the influence of endothelial dysfunction on the development of intimal thickening, we prospectively analyzed the vasomotor response to acetylcholine and nitroglycerin, as well as other donor and recipient variables. Findings were correlated with the coronary intimal thickness, which was evaluated by means of intravascular ultrasonography. METHODS: Nineteen patients who had undergone heart transplantation 4.89 +/- 2.35 years previously and who had angiographically normal coronary arteries were included. Endothelial function was analyzed by quantitative coronary analysis of the vasomotor response of the left anterior descending artery to acetylcholine. An intimal thickness index, reflecting the percentage of intima obstructing the coronary lumen, was calculated. RESULTS: Nine (47%) patients showed endothelial dysfunction, and the remaining 10 (53%) patients had a normal response. Four (44%) of 9 patients with a weight gain of greater than 20% after the operation showed endothelial dysfunction compared with none of the 10 patients with normal responses (P <.04). The severity of the intimal thickness correlated with the years after transplant (r = 0.45, P <.05). Patients with endothelial dysfunction had more intimal thickening than those without (32% +/- 17% vs 17% +/- 12%, respectively; P <.05). Furthermore, the degree of intimal thickening correlated with the magnitude of the vasomotor response to acetylcholine (r = -0.60, P =.006). No relationship was found between intimal thickness and the vasodilatory response to nitroglycerin. As independent variables for intimal thickness, multivariate analysis detected the magnitude of the response to acetylcholine (P =.0005), years after transplant (P =.01), and ischemic time (P =.03). CONCLUSIONS: Cardiac allograft vasculopathy is a multifactorial disease the severity of which increases over time. Endothelial dysfunction is a predictive factor of intimal thickening severity. Predisposing factors that provoke endothelial injury, such as perioperative ischemic time and obesity, may contribute to the development of allograft vasculopathy.     

Endothelin in coronary endothelial dysfunction early after human heart transplantation.

BACKGROUND: Cytokines and growth factors released as part of the immune response to alloantigenic stimuli are capable of regulating endothelin-1 expression in the allograft. Endothelin plays a significant role as a modulator of coronary vascular reactivity in the early stages of atherosclerosis and may be important as a participant in and marker for cardiac allograft vasculopathy. METHODS: We characterized a possible relationship between morphological and functional coronary changes, transcardiac plasma endothelin level and myocardial endothelin-mRNA expression in 33 cardiac transplant recipients in the early, stable phase 5+/-3 months after orthotopic heart transplantation. Coronary microvascular function was determined as endothelium-dependent with acetylcholine and endothelium-independent with adenosine using intracoronary Doppler-FloWire. The percentage of the epicardial diameter changes was measured using quantitative coronary angiography. Intravascular ultrasound was performed to quantify intimal hyperplasia. Cardiac endothelin uptake or release was determined by measuring plasma endothelin levels in the coronary sinus and aorta. Myocardial endothelin-gene expression was determined using semiquantitative RT-PCR. RESULTS: The aortic endothelin levels were significantly increased in transplant recipients compared to nontransplanted patients (11.8+/-2.2 vs 7.2+/-0.9 fmol/mL; P < 0.001). Endothelin uptake was noticed in the majority of patients, and the amount of endothelin uptake was correlated to microvascular (r = 0.37; P < 0.05) and epicardial (r = 0.41; P < 0.03) endothelium-dependent vasodilatation. High mRNA signal intensity was associated with significantly reduced coronary flow response to acetylcholine compared to patients with low myocardial gene expression (coronary flow reserve 2.4+/-0.9 vs 3.4+/-0.8, respectively; P < 0.005). Morphological coronary changes early after transplantation were not correlated to endothelin plasma levels or myocardial gene expression. CONCLUSION: Coronary endothelial vasomotor dysfunction after cardiac transplantation is associated with an increased myocardial endothelin mRNA expression and decreased endothelin-uptake by the heart. We postulate that early activation in the endothelin system may have a pivotal role in the acceleration of the atherosclerotic process in transplant patients.     

Is all intimal proliferation created equal in cardiac allograft vasculopathy? The quantity-quality paradox.

BACKGROUND: Pre-angiographic detection of intimal proliferation using intravascular ultrasound in heart transplant recipients has focused investigators' attention on the prognostic utility of such early information. Not all heart transplant recipients who exhibit a "prognostically relevant" threshold of severe (>0.5 mm) intimal thickening experience cardiac events. We sought to contrast clinical characteristics of heart transplant recipients who have prognostically relevant, severe intimal proliferation and who experience cardiac events with those who remain event free. METHODS: We prospectively followed an inception cohort of 54 consecutive heart transplant recipients with severe intimal proliferation (intimal thickness >0.5mm) of the coronary arteries after index intravascular ultrasound examination to assess the development of cardiac events (sudden cardiac death, myocardial infarction) and/or the necessity for coronary revascularization with percutaneous techniques (angioplasty, atherectomy, stent implantation) or surgical bypass. RESULTS: Based on the occurrence of adverse cardiac events during the subsequent 24 months, we divided the study cohort into 2 groups: Group 1 (no event, n = 33) and Group 2 (cardiac event, n = 21). Both groups demonstrated similar intimal thickness at the index ultrasound (Group 1, 0.89 +/- 0.27 mm, vs Group 2, 0.94 +/- 0.36 mm; p = not significant). Those with cardiac events were more likely than those without events to have hyperlipidemia, to have greater exposure to cumulative and average daily prednisone, and to exhibit greater average biopsy rejection scores at follow-up. CONCLUSIONS: These observations underscore the importance of the quality and not merely the quantity of intimal proliferation in determining occurrence of morbid cardiac events and further emphasize the interaction of immunologic and non-immunologic factors in determining event vulnerability in cardiac allograft vasculopathy.     

Inhibiting the NO pathway with intracoronary L-NAME infusion increases endothelial dysfunction and intimal hyperplasia after heart transplantation.

BACKGROUND: The endothelium protects the vascular wall through the nitric oxide (NO) release. Coronary endothelial dysfunction occurs early after heart transplantation and predicts the development of intimal thickening typical of graft coronary vasculopathy. OBJECTIVE: We designed this study to examine the effect of endothelial NO synthase (eNOS) inhibition on the endothelial dysfunction caused by rejection and on the development of accelerated atherosclerosis after heart transplantation. METHODS: To study the effect on these 2 end-points of inhibiting eNOS with intracoronary L-nitro arginine methyl ester (L-NAME; 1 mg/kg/day), infused with an osmotic pump for 30 days, we used a porcine model of heterotopic heart transplantation with pre-operative immunologic typing, to permit slow rejection without the need for immunosuppression. The endothelium-dependent relaxations of allografted coronary arteries, allografted arteries infused with L-NAME, allografted arteries mounted with the pump, and vehicle and native coronary arteries were compared 30 days after graft implantation using standard organ chamber experiments. We evaluated intimal thickening using a semi-quantitative scale (0-4+ grading). RESULTS: A significant decrease in relaxations to serotonin (5-HT) occurred in allografted arteries infused directly with L-NAME compared with allografted arteries from swine receiving 5-HT, and relaxations in the latter were decreased compared with those of swine receiving the vehicle and native coronary arteries (p < 0.05). We found no significant differences in endothelium-dependent relaxations to bradykinin among coronary rings from all groups. We observed a significant increase in the prevalence and severity of intimal thickening in allografted coronary arteries infused with L-NAME compared with allografts not infused (p < 0.05), which had significantly more intimal thickening compared with native coronary arteries (p < 0.05). CONCLUSION: These results demonstrate that inhibiting the NO pathway worsens the endothelial dysfunction caused by rejection after heart transplantation and accelerates the intimal thickening process, leading to graft coronary vasculopathy. Strategies designed to preserve endothelial integrity and function of the endothelial NO pathway should be used to prevent graft coronary vasculopathy.     

The topography of intimal thickening and associated remodeling pattern of early transplant coronary disease: influence of pre-existent donor atherosclerosis.

BACKGROUND: With native coronary disease, intimal plaque initially accumulates at focal areas in the artery, often accompanied by compensatory vessel enlargement. With transplant coronary disease, the topography of intimal thickening and associated remodeling pattern are less studied. METHODS: We studied 72 prospectively recruited transplant patients with serial intravascular ultrasound using 4.3F catheters at baseline and at 1-year follow up. We considered 175 ultrasound-recorded segments (mean, 2.4 +/- 1.1 segments per patient) exactly matched on the serial studies by both angiographic criteria and ultrasound criteria, using arterial and venous branch points, pericardium, and sinuses as anatomic landmarks. RESULTS: Eighty-eight segments had no donor disease, and 87 had donor disease (80 eccentric and 7 concentric intimal thickening). Progressive intimal thickening occurred in 48 segments without (55%) and 43 segments with donor disease (48%, p = NS). Thickening from segments without donor disease was mainly eccentric (81%). Thickening from segments with donor eccentric plaque was also mainly eccentric (67%, p = NS compared with segments without donor disease), with further thickening superimposed on the original plaque. Concentric intimal thickening was uncommon. Of the 58 patients who had >1 segment matched, intimal changes were discordant in 34 (59%), with progression in some and lack of progression in other segments. Total vessel area change correlated with intimal area change (r = 0.37 with a slope of 0.79, p < 0.001), including segments with (r = 0.39; slope, 0.69) and segments without (r = 0.37; slope, 1.16) donor disease. CONCLUSION: The intimal thickening of early transplant coronary disease is mainly eccentric and often discordant within each individual patient. Donor eccentric plaque often serves as a nidus for further intimal growth. The topography of intimal thickening in transplant coronary disease resembles that of native coronary disease, but the presence of a pre-existent donor plaque may impede compensatory remodeling as further intimal thickening occurs after transplantation.     

Role of vascular remodeling in the pathogenesis of early transplant coronary artery disease: a multicenter prospective intravascular ultrasound study.

BACKGROUND: Luminal narrowing in transplant coronary artery disease is thought to be primarily caused by intimal proliferation, and the role of vascular remodeling is less certain. METHODS AND RESULTS: We studied cardiac allografts from 83 prospectively recruited patients immediately and 1 year after transplant using intravascular ultrasound in a multicenter study. We measured coronary artery dimensions in 310 angiographically matched segments (175 were also fully matched by ultrasound criteria). At 1 year, lumen area changed by -1.8 +/- 3.7 mm(2) (p < 0.0001, 14% of baseline lumen area). Thirty-three percent of this luminal loss was due to intimal thickening and 67% to vessel shrinkage. Shrinkage also occurred (-0.9 +/- 3.2 mm(2), 7% of baseline total area) in segments free of detectable intimal disease at baseline and at 1 year. Using the mean baseline total vessel area (13.9 mm(2)) as the cutoff, we divided the cohort into the large and the small coronary-segment groups. The large-segment group (n = 176) shrank more (-2.6 +/- 4.4 vs. -0.03 +/- 2.8 mm(2), p < 0.0001), but intimal growth was similar in both groups (0.8 +/- 2.2 vs. 0.4 +/- 1.3 mm(2), p = not significant). Analysis of the 175 fully ultrasound matched sub-cohort showed similar results. Changes in intimal area, total vessel area, and lumen area were similar in segments with (n = 132) and segments without (n = 178) pre-existing donor disease. Despite overall shrinkage, change in total vessel area positively correlated with change in intimal area (r = 0.29, p < 0.0001). CONCLUSION: In large coronary segments, coronary artery shrinkage plays an important role in the loss of luminal diameter early after cardiac transplantation, whereas new intimal growth occurs in both large and small segments. Pre-existent donor disease does not aggravate these processes. Compensatory remodeling with increasing intimal growth retards the rate of lumen loss. As is intimal thickening, shrinkage and compensatory remodeling are important pathogenic mechanisms in transplant coronary artery disease.     

Early constriction or expansion of the external elastic membrane area determines the late remodeling response and cumulative lumen loss in transplant vasculopathy: an intravascular ultrasound study with 4-year follow-up.

BACKGROUND: Early constriction of the external elastic membrane (EEM) area has been observed after cardiac transplantation. The aim of this study was to compare the late disease process of transplant vasculopathy between coronary segments with early constrictive and expansive remodeling. METHODS: Serial intravascular ultrasound data obtained annually for 4 years after transplantation in 38 transplant recipients was available. In 135 matched segments from 59 coronary arteries ultrasound images were digitized at 1-mm intervals. Mean values of the external elastic membrane (EEM), lumen and intimal areas were calculated. On the basis of a decrease or increase in EEM area within the first year after transplantation, we defined segments with early constrictive remodeling (CR, n = 71) or early expansive remodeling (ER, n = 64). RESULTS: Annual changes in intimal area were similar between segments with early CR and ER throughout the follow-up period. However, during the second and third year, annual increases in EEM area were greater in segments with early CR than in segments with early ER (second year: 1.5 +/- 2.7 vs 0.6 +/- 2.8 mm(2), p = 0.052; third year: 1.3 +/- 2.5 vs -0.03 +/- 2.6 mm(2), p = 0.003). Despite this late expansion, segments with early CR showed a cumulative decrease in the EEM area and a greater lumen loss than segments with early ER (-2.5 +/- 3.4 vs -0.6 +/- 2.6 mm(2), p < 0.001). CONCLUSIONS: In transplant vasculopathy, the late remodeling response was different between segments with early constrictive and expansive remodeling, despite similar intimal thickening. Early constriction caused an overall decrease in EEM area and greater loss of lumen during follow-up.     

The influence of donor gender on allograft vasculopathy: evidence from intravascular ultrasound

BACKGROUND: Allograft vasculopathy is a major risk factor for mortality following cardiac transplantation. Several immune and nonimmune factors have been evaluated as risk factors for the development of coronary vasculopathy. OBJECTIVE: We evaluated the influence of donor gender on the progression of coronary vasculopathy in heart transplant recipients. METHODS: Eighty-nine heart transplant recipients (67 men, 22 women of mean age: 56 +/- 12 years) underwent serial volumetric intravascular ultrasound analysis (IVUS) at baseline (within 1 month) and at 1 year after transplantation. Patients were divided into four groups in relation to the donor-recipient gender status: female-female, n=17; female-male, n=28; male-female, n=5; male-male, n=39. Ultrasound images were recorded during an automated pullback and with an equal number of slices (average=22 per coronary vessel). The measured IVUS indices for the left anterior descending artery were: change in maximal intimal thickness, average intimal area, total plaque volume, and intimal index. RESULTS: Patients were similar in baseline characteristics. At 1 year after transplantation, IVUS indices of coronary vasculopathy were significantly increased among recipients of female allografts (P <.05). CONCLUSION: Heart transplant recipients of female allografts display increased coronary vasculopathy progression.     

Donor intracranial bleeding is associated with advanced transplant coronary vasculopathy: evidence from intravascular ultrasound

OBJECTIVES: We evaluated the impact of spontaneous intracranial bleeding (ICB) in the donor on transplant coronary vasculopathy using serial intravascular ultrasound examinations. MATERIALS AND METHODS: Between January 1995 and December 2000, 72 recipients underwent cardiac transplantation from donors who had experienced spontaneous ICB (ICB group). Their findings using serial intravascular ultrasound analysis at baseline (within 1 month) and 1 year after transplantation were compared with 90 recipients who had undergone transplantation from trauma donors (trauma group). RESULTS: Compared with the Trauma group, the ICB group showed increased coronary intimal thickness (0.55 +/- 0.33 vs 0.39 +/- 0.3 mm; P = .034), plaque volume (3.84 +/- 2.5 vs 2.28 +/- 1.65 mm(3); P = .015) and plaque burden (7.4 vs 2%) at 1 year after transplantation. CONCLUSIONS: Donor spontaneous ICB is associated with significantly increased coronary vasculopathy.     

Quilty lesions are associated with increased expression of vitronectin receptor (alphavbeta3) and subsequent development of coronary vasculopathy.

BACKGROUND: Quilty lesions are common after heart transplantation; however, their relationship to vasculopathy has not been described. We tested the hypothesis that Quilty lesions are associated with increased expression of vitronectin receptor (alphavbeta3) and the subsequent development of coronary vasculopathy. METHODS: A total of 140 heart transplant recipients underwent coronary intravascular ultrasound at baseline and at 1 year after transplantation, and we measured the change in coronary maximal intimal thickness. Endomyocardial biopsy specimens taken within 8 weeks after transplantation showed Quilty lesions in 54 of 140 (39%) patients (Quilty group). We compared these results with the remaining 86 of 140 patients (61%) who had no evidence of Quilty lesions during the same period (control group). We evaluated 10 endomyocardial biopsy specimens from each group for alphavbeta3, using immunohistochemistry staining and immunoblotting. RESULTS: Quilty lesions stained positive for alphavbeta3, and Western blot analysis showed a 1.3-fold (p = 0.004) increase in expression of alphavbeta3. Compared with control, the Quilty group tended to have a greater incidence of post-transplant ischemic injury complicated by fibrosis (54% vs 38%, p = 0.08) and a greater reported incidence of "previous biopsy site" during the first 4 weeks after transplantation (48% vs 32%, p = 0.06). At 1 year, the Quilty group had a significant increase in the change in coronary maximal intimal thickness seen with intravascular ultrasound (0.54 +/- 0.34 vs 0.42 +/- 0.28 mm, p = 0.038). CONCLUSIONS: This is the first report to describe the association of Quilty lesions with coronary vasculopathy and its association with increased alphavbeta3 expression.     

Injury of the coronary endothelium at implantation increases endothelial dysfunction and intimal hyperplasia after heart transplantation.

BACKGROUND: Coronary endothelial dysfunction occurs early after heart transplantation and predicts the development of intimal thickening characteristic of cardiac allograft vasculopathy. OBJECTIVES: To assess the effects of removal of the endothelium by balloon injury of coronary arteries of allografts without rupture of the internal elastic lamina at the time of implantation and on coronary endothelial dysfunction, and to assess the development of accelerated atherosclerosis after heart transplantation. METHODS: A porcine model of heterotopic heart transplantation with preoperative immunologic typing, enabling progressive rejection without immunosuppression, was used to study the effect of endothelial removal on these 2 end points. Endothelium-dependent relaxations of epicardial coronary arteries from allografts submitted to endothelial denudation after harvest, arteries from allografts not undergoing denudation, and native coronary arteries were compared 30 days after graft implantation by using standard organ chamber experiments. Intimal thickening was measured by light microscopy with a semiquantitative scale (0 to 4+ grading). RESULTS: Relaxations to serotonin and to bradykinin were significantly decreased in denuded arteries compared with nondenuded allograft arteries. There was a significant increase in the incidence of severe intimal hyperplasia in denuded arteries compared with nondenuded arteries, which were both significantly increased compared to native coronary arteries. CONCLUSIONS: Endothelial injury at implantation worsens the endothelial dysfunction as a result of rejection after heart transplantation and compounds the intimal thickening leading to cardic allograft vasculopathy. All efforts should be deployed to maintain a morphologically intact and functional endothelium at the time of graft implantation.     

Relevance of cytomegalovirus infection and coronary-artery remodeling in the first year after heart transplantation: a prospective three-dimensional intravascular ultrasound study

BACKGROUND: Transplant coronary artery disease (TxCAD) is a major cause of long-term mortality after heart transplantation. Although vascular remodeling has been implicated in the pathophysiology of TxCAD, its determinants remain unknown. METHODS: Twenty-nine consecutive heart-transplant recipients prospectively received intravascular ultrasound (IVUS) of the left-anterior descending artery 1 and 12 months after transplant, with volumetric reconstruction of the proximal 30 mm. RESULTS: Overall, patients exhibited intimal volume increase (+83%, P<0.001), wheras vessel volume remained largely unchanged (+4%, P=0.270); consequently, overall lumen volume decreased (-6%, P=0.058). Among the clinical and laboratory variables, cytomegalovirus (CMV) infection requiring treatment (occurring in 12 patients), as assessed by pp65 antigenemia, was independently associated with the impaired ability of the vessel wall to enlarge in response to intimal volume increase, ultimately resulting in lumen loss (OR [95% CI]=0.098 [0.010-0.920]; P=0.042). However, adequate vessel response to intimal hyperplasia with consequent lumen preservation was observed in the remaining 17 patients who did not present CMV infection requiring treatment. CONCLUSIONS: The present study demonstrates that either adequate or inadequate coronary remodeling may occur during the first year after transplantation. Moreover, for the first time, it strongly suggests that remodeling modalities may be negatively influenced by the occurrence of clinically relevant CMV infection. Randomized prospective trials are warranted to investigate whether aggressive treatment of CMV infection may help prevent TxCAD.     

心脏移植长期存活患者冠状动脉病变一例

目的　探讨 1例心脏移植长期存活患者冠状动脉病变的原因、诊断和处理。方法　对1例心脏移植术后存活 8年的患者进行长期随访。结果　术后患者生活质量好 ,恢复正常工作 ;血液生化正常 ;心电图无心肌缺血改变 ;肱动脉内皮依赖性血管舒张功能正常 ;心内膜心肌活检未见急性排斥反应征象 ;同位素心肌显像提示左室壁心肌放射性分布进行性减低 ;冠状动脉造影显示左冠状动脉弥漫性狭窄、右冠状动脉近段有一局限性严重狭窄 (>90 % )、远端为轻度弥漫性狭窄 ,行右冠状动脉近段成形和支架植入 ,同位素心肌显像示左室壁心肌放射性分布明显改善。结论　慢性排斥反应可能是导致移植心冠状动脉病变的重要原因 ;定期行同位素心肌显像检查有助于了解心肌血液供应 ;严重的局限性冠状动脉病变可应用冠状动脉成形和支架植入予以治疗。     

Effects of inosine on reperfusion injury after heart transplantation.

OBJECTIVE: Inosine, a break-down product of adenosine, has been recently shown to exert inodilatory and anti-inflammatory properties. We investigated the effects of inosine on ischemia/reperfusion injury in a rat heart transplantation model. METHODS: Intraabdominal heterotopic transplantation was performed in Lewis rats. After 1h of ischemic preservation, reperfusion was started after application of either saline vehicle (control, n=12) or inosine (100 mg/kg, n=12). Coronary blood flow, left ventricular function, endothelium-dependent vasodilatation to acetylcholine and endothelium-independent vasodilatation to sodium nitroprusside, and high energy phosphate content were measured after 1 and 24h of reperfusion. In addition, the activation of the poly(ADP-ribose) polymerase was detected by immunhistology. RESULTS: After 1h, coronary blood flow (4.1+/-0.3 ml/(ming) vs 2.9+/-0.3 ml/(ming), p<0.05), left ventricular systolic pressure (102+/-9 mmHg vs 83+/-4 mmHg, p<0.05) and dP/dt (2765+/-609 mmHg/s vs 1740+/-116 mmHg/s, p<0.05) were significantly higher in the inosine group in comparison to control. Vasodilatatory response to sodium nitroprusside was similar in both groups. Acetylcholine resulted in a significantly higher increase in coronary blood flow in the inosine group (76+/-5% vs 48+/-9%, p<0.05). Energy charge potential was significantly higher in the inosine group (1.69+/-0.10 micromol/g vs 0.74+/-0.27 micromol/g, p<0.05). After 24h, there was no difference between the groups in basal coronary blood flow, left ventricular systolic pressure, dP/dt, and the response to sodium nitroprusside. However, acetylcholine led to a still significantly higher response in the inosine group (112+/-13% vs 88+/-7%, p<0.05). Immunhistologic stainings revealed activation of poly(ADP-ribose) polymerase in control animals which was abolished by inosine. CONCLUSIONS: Thus, inosine improves myocardial and endothelial function during early reperfusion after heart transplantation with a persisting beneficial effect against reperfusion induced graft coronary endothelial dysfunction. The effects of inosine are mediated at least partly by modulation of the peroxynitrite-poly(ADP-ribose) polymerase pathway.     

Impairment in forearm endothelium-dependent vasodilation after heart transplantation

BACKGROUND: Endothelial dysfunction has been found in the peripheral circulation of patients with severe heart failure. However, whether the endothelial dysfunction improves after heart transplantation remains unknown. Our aim was to assess the forearm endothelium-dependent vasoreactivity one and six months after heart transplantation. METHODS: We studied 12 patients using high resolution brachial artery ultrasound to assess flow-mediated dilation induced by reactive hyperemia and nitroglycerin induced dilation (NTGdil). RESULTS: One month after heart transplantation, endothelium-dependent vasodilation was significantly impaired in 10 patients (83%), while it was preserved in the remaining two (17%) (0.4%+/-2.4% vs 9.9%+/-4.6%, respectively, P=.001). NTGdil was normal in both groups (12%+/-10% vs 23%+/-5%, respectively, P=NS). At six months, endothelial dysfunction was present in all patients including the two patients without endothelial dysfunction at the first study. CONCLUSIONS: The present study demonstrates that peripheral endothelial dysfunction is present after heart transplantation despite the improvement in left ventricular function. More studies are needed to prove if endothelial dysfunction reversion may improve survival in heart transplantation.     

Quantitative analysis of nitroglycerin-induced coronary artery vasodilation in transplanted hearts.

Quantitative serial coronary angiograms performed annually over a 3-year period after transplantation in 26 orthotopic heart transplant recipients showed persistently normal nitroglycerin-induced vasodilation. The vasodilator response to nitroglycerin did not predict development of graft arteriopathy; the presence of graft arteriopathy did not prevent a substantial vasodilator response to nitroglycerin.     

Longitudinal study of vascular remodeling in coronary arteries after heart transplantation.

Cross-sectional studies by intravascular ultrasound (IVUS) in heart transplant recipients have suggested that vascular remodeling occurs in coronary arteries years after transplant. However, no reports describe vascular remodeling in the same cohort of patients studied prospectively using morphometric analysis (10 evenly spaced images obtained from a slow pullback from the left anterior descending coronary artery). Morphometric analysis better reflects total vessel anatomy compared with previously reported site (2 to 3 images) analysis.We reviewed 20 patients studied by IVUS at 2 months, 1 year, 2 years, and 3 years after heart transplant.Over time, the coronary artery luminal area decreased from baseline level of 12.0 mm(2) to a 3-year mark of 9.7 mm(2) (p = 0.02). Vessel shrinkage was seen in 16/20 patients. After an initial rise in intimal parameters (maximal intimal thickness, intimal index, and plaque area) from baseline to 1 year, we found a significant decrease in intimal parameters between Year 1 and Year 3 after transplant. For example, plaque area decreased from 2.05 mm(2) at 1 year post-transplant to 1.48 mm(2) by 3 years post-transplant (p = 0.05).In a majority of heart transplant patients, early intimal thickening in the first year post-transplant is accompanied by constrictive remodeling. Over the subsequent 2 years, further constrictive remodeling is seen despite a decrease in intimal area.     

Intimal hyperplasia and coronary flow reserve after heart transplantation: association with big endothelin-1

BACKGROUND: Endothelin, a peptide with strong vasoconstrictive and mitogenic properties, has been found to increase after cardiac transplantation. We therefore assessed the association between its precursor peptide, big endothelin-1, and intimal hyperplasia and coronary flow reserve after heart transplantation. METHODS: Thirty-five patients without hemodynamically significant coronary artery disease after heart transplantation were investigated: Average peak flow velocity in the left anterior descending artery (LAD) was assessed by intracoronary Doppler at baseline as well as after injection of adenosine; coronary flow reserve was calculated as a ratio of both and was corrected for patient age and baseline average peak flow velocity. Lumen, intima + media and total vessel area were measured by intracoronary ultrasound. The plasma concentration of big endothelin-1 in venous blood was determined by radioimmunoassay. RESULTS: Patients with elevated big endothelin-1 levels (>2 fmol/ml) tended to have a decreased corrected coronary flow reserve (2.60 +/- 0.9 vs 3.21 +/- 1.0, p = 0.078). They also had a significantly larger intima + media area (5.82 +/- 2.9 vs 2.37 +/- 2.9 mm(2), p = 0.004) and total vessel area (18.36 +/- 5.8 vs 12.81 +/- 4.8 mm(2), p = 0.012) than those with normal plasma concentrations. CONCLUSIONS: Our study suggests an association between elevated big endothelin-1 plasma levels and the development of intimal hyperplasia and reduction of coronary flow reserve after cardiac transplantation.