Coronary Flow Reserve by Contrast-Enhanced Echocardiography: A New Noninvasive Diagnostic Tool for Cardiac Allograft Vasculopathy

Noninvasive tests have proven unsatisfactory in cardiac allograft vasculopathy (CAV) diagnosis. We assessed coronary flow reserve (CFR) by contrast-enhanced transthoracic echocardiography (CE-TTE) in heart transplantation (HT). CFR was assessed in the left anterior descending coronary artery in 73 HT recipients (59 male, aged 50 ± 12 years at HT), at 8 ± 4.5 years post-HT. CFR measurements were taken blindly from coronary angiographies. CFR cut points were the standard value of ≤2 and those defined by receiver operating characteristics (ROC) curve analysis. CFR was lower in patients with CAV (2.3 ± 0.7 vs. 3.2 ± 0.5, p < 0.0001). The ≤2 cut point was 100% specific and 38% sensitive. The ≤2.7 cut point, optimal by ROC analysis, was 87% specific and 82% sensitive. Accuracy rose from 71% with the standard ≤2 cut point to 85% with the optimal cut point of ≤2.7. CFR by CE-TTE may offer promise as a novel, easily repeatable and accurate noninvasive tool in CAV detection. However, further longitudinal studies in larger patient cohorts are warranted before widespread adoption can be advocated.     

Coronary Flow Reserve by Transthoracic Echocardiography Predicts Epicardial Intimal Thickening in Cardiac Allograft Vasculopathy

Cardiac allograft vasculopathy (CAV) is the leading cause of morbidity and mortality in heart transplantation (HT). We sought to investigate the role of coronary flow reserve (CFR) by contrast‐enhanced transthoracic echocardiography (CE‐TTE) in CAV diagnosis. CAV was defined as maximal intimal thickness (MIT) assessed by intravascular ultrasound (IVUS) ≥0.5 mm. CFR was assessed in the left anterior descending coronary artery in 22 HT recipients at 6 ± 4 years post‐HT. CAV was diagnosed in 10 patients (group A), 12 had normal coronaries (group B). The mean MIT was 0.7 ± 0.1 mm (range 0.03–1.8). MIT was higher in group A (1.16 ± 0.3 mm vs. 0.34 ± 0.07 mm, p < 0.0001). CFR was 3.1 ± 0.8 in all patients and lower in group A (2.5 ± 0.6 vs. 3.7 ± 0.3, p < 0.0001). CFR was inversely related with MIT (r =?0.774, p < 0.0001). A cut point of ≤2.9, identified as optimal by receiver operating characteristics analysis was 100% specific and 80% sensitive (PPV = 100%, NPV = 89%, Accuracy = 91%). CFR assessment by CE‐TTE is a novel noninvasive diagnostic tool in the detection of CAV defined as MIT ≥0.5 mm. CFR by CE‐TTE may reduce the need for routine IVUS in HT.     

Macrophage Depletion Suppresses Cardiac Allograft Vasculopathy in Mice

Cardiac allograft vasculopathy (CAV) is a major source of late posttransplant mortality. Although numerous cell types are implicated in the pathogenesis of CAV, it is unclear which cells actually induce the vascular damage that results in intimal proliferation. Because macrophages are abundant in CAV lesions and are capable of producing growth factors implicated in neointimal proliferation, they are leading end-effector candidates. Macrophages were depleted in a murine heterotopic cardiac transplant system known to develop fulminant CAV lesions. C57BL/6 hearts were transplanted into (C57BL/6 x BALB/c)F(1) recipients, which then received anti-macrophage therapy with intraperitoneal carrageenan or i.v. gadolinium. Intraperitoneal carrageenan treatment depleted macrophages by 30-80% with minimal effects upon T, B or NK cells as confirmed by flow cytometry and NK cytotoxicity assays. Carrageenan treatment led to a 70% reduction in the development of CAV, as compared to mock-treated controls (p = 0.01), which correlated with the degree of macrophage depletion. Inhibition of macrophage phagocytosis alone with gadolinium failed to prevent CAV. Macrophages may represent the end-effector cells in a final common pathway towards CAV independent of T-cell or B-cell alloreactivity and exert their injurious effects through mechanisms related to cytokine/growth factor production rather than phagocytosis.     

The Role of Viruses in Cardiac Allograft Vasculopathy

Considerable evidence suggests a role for viruses in transplant arteriosclerosis (TA), including observational data, experimental models and therapeutic trials implicating human cytomegalovirus (HCMV) in the progression to TA. In pediatric heart transplant patients, adenoviral genome in endomyocardial biopsies (EMB) is an important predictor of TA and graft loss. During CMV viremia, EMBs from adult patients demonstrate endothelialitis and vascular smooth muscle cell proliferation. These changes are predictors of subsequent diffuse TA. HCMV immediate early proteins (IE-1 and IE-2) increase the constitutive expression of intercellular adhesion molecule-1 (ICAM-1) independent of other intracellular cytokines. Likewise, viral chemokines such as US28 have been implicated in vascular disease because of their ability to induce smooth muscle cell migration. Recent data suggests that CMV might accelerate TA through its ability to abrogate the vascular protective effects of the endothelium-derived nitric oxide system (eNOS). Confirmation of causality requires clinical trials demonstrating that antiviral agents such as ganciclovir inhibit TA. Such studies in patients though limited to retrospective analyses, suggest that ganciclovir prophylaxis early after heart transplantation reduces the risk of TA. These observations emphasize the need for randomized controlled clinical trials to confirm a causal role for CMV (and other viruses) in TA.     

Contemporary Concepts in Prevention and Treatment of Cardiac Allograft Vasculopathy

Cardiac allograft vasculopathy (CAV), is characterized by heterogeneous proliferative thickening of the vascular intima of the cardiac allograft vasculature. Since its presentation is commonly clinically silent, early diagnosis and preventative therapy are critical. Preventative therapy including optimization of immunosuppressive therapy and treatment of comorbidities associated with CAV progression must be initiated early since most of the intimal thickening occurs during the first year posttransplant. Long-term use of calcineurin inhibitors is associated with a high incidence of chronic renal disease and also contributes to hyperlipidemia and hypertension, all of which may exacerbate CAV. In addition, statins, antihypertensive agents and anti-CMV agents all have demonstrated benefits in reducing CAV. Once established, the limited treatment options include nonpharmacologic interventions such as retransplantation, percutaneous coronary interventions, coronary artery bypass grafting, transmyocardial laser revascularization and heparin-induced/mediated extracorporeal LDL plasmapheresis (HELP). As the use of new assessment tools increases our understanding of this disease, better preventative and treatment strategies are evolving.     

Coronary Microvascular Dysfunction Correlates With the New Onset of Cardiac Allograft Vasculopathy in Heart Transplant Patients With Normal Coronary Angiography

Coronary microvascular dysfunction is emerging as a strong predictor of outcome in heart transplantation (HT). We assessed the validity of microvascular dysfunction, defined by means of a reduced coronary flow reserve (CFR), as a factor associated with new onset epicardial cardiac allograft vasculopathy (CAV) or death. We studied 105 patients at 4 ± 1 years post‐HT with a normal coronary angiography (CA). New onset CAV was assessed by CA. CFR was assessed in the left anterior descending (LAD) coronary artery by transthoracic Doppler echocardiography and calculated as the ratio of hyperaemic to basal blood flow velocity. A CFR ≤ 2.5 was considered abnormal. Epicardial CAV onset or death was assessed during a follow‐up of 10 years. New onset CAV was diagnosed in 30 patients (28.6%) (Group A), and the CA was normal in the remaining 75 patients (71.4%) (Group B). Group A had reduced CFR compared with group B (2.4 ± 0.6 vs. 3.2 ± 0.7, p < 0.0001). A CFR ≤ 2.5 was independently associated with a higher probability of new onset CAV (p < 0.0001) and a higher probability of death, regardless of CAV onset (p < 0.01). Microvascular dysfunction is independently associated with the onset of epicardial CAV, and associated with a higher risk of death, regardless of CAV onset.     

Early Prediction of Cardiac Allograft Vasculopathy and Heart Transplant Failure

Early risk‐prediction is essential to prevent cardiac allograft vasculopathy (CAV) and graft failure in heart transplant patients. We developed multivariate models to identify patients likely to experience CAV, severe CAV, and failure due to CAV, at 1, 5 and 10 years. A cohort of 172 patients was followed prospectively for 6.7 ± 3.9 years. Logistic regression models were developed and cross‐validated using bootstrap resampling. Predictive markers of atherothrombosis (myocardial fibrin deposition, and loss of vascular antithrombin and tissue plasminogen activator) and arterial endothelial activation (intercellular adhesion molecule‐1 expression) were measured in serial biopsies obtained within 3 months posttransplant. Most markers were univariately associated with outcome. Multivariate models showed that loss of tissue plasminogen activator was the dominant and, in most cases, only predictor of long‐term CAV (p < 0.001), severe CAV (p < 0.001), and graft failure due to CAV (p < 0.001). The models discriminated patients having adverse outcomes, had particularly high negative predictive values (graft failure due to CAV: 99%, 99% and 95% at 1, 5 and 10 years) and predicted event incidence and time to event. Early absence of atherothrombotic risk identifies a patient subgroup that rarely develops CAV or graft failure, implying that this low‐risk subgroup could possibly be followed with fewer invasive procedures.     

大鼠腹腔心脏移植术后移植物血管病模型的建立

目的探讨建立大鼠腹腔心脏移植物血管病动物模型的方法。方法将40只W istar大鼠和40只SD大鼠随机配对分为对照组和实验组,建立大鼠的异位心脏移植;对照组不注射环孢霉素A(C sA),实验组腹腔注射小剂量的C sA,两组分别于移植术后2周和4周切取移植心脏,在光学显微镜下观察移植心脏冠状血管的改变。结果对照组术后2周和4周冠状血管内膜无变化;实验组术后2周冠状血管内膜增厚,4周后冠状血管内膜成同心圆样改变,管腔明显狭窄,出现移植后移植物血管病改变。结论该模型是一种可靠的移植物血管病的动物模型。     

Characteristics of Cardiac Allograft Vasculopathy Induced by Immunomodulation in the Miniature Swine

Purpose: We aimed to develop swine cardiac transplantation model for study of cardiac allograft vasculopathy (CAV) and to characterize the mechanisms of its formation.Methods: Heterotropic cardiac transplantation was performed in swine leukocyte antigen mismatched miniature swine, and CAV was induced by immunomodulation by cyclosporine A (CyA). Histology and immunohistochemistry were performed to identify cellular components of CAV. Fluorescence in situ hybridization (FISH) was developed for detection of 1 and Y-chromosome for identification of cell origin in the female donor to the male recipient heart transplantation model.Results: CAV was successfully developed by immunomodulation of CyA. Severity of CAV revealed more prominent in the distal epicardial coronary arteries than proximal coronary arteries. Phenotype of the SMCs proliferated in the intimal thickening of CAV were mostly embryonal/secretory type. Our new chromosome specific probes for FISH method were useful for discrimination of sex of each cell, and proliferated SMCs were revealed to be mainly donor origin.Conclusion: CAV mimicking human heart transplantation can be developed by appropriate immunomodulation in the swine. In swine CAV, proliferated SMCs seen in the intimal thickening were demonstrated to be from the donor origin.