Cardiac Transplant Vasculopathy Research Articles

Decreased Global Myocardial Work Efficiency Correlates with Coronary Vasculopathy in Pediatric Heart Transplant Patients.

Coronary angiography remains the standard for diagnosis of cardiac transplant vasculopathy (CAV), but it is invasive. Non-invasively derived left ventricle (LV) global myocardial work (GMW) indices have not been evaluated. We aimed to assess for correlations between LV GMW and the presence of CAV in a pediatric population. 24 heart transplant patients and 24 normal controls were prospectively enrolled. Patients were age-matched into groups with: orthotopic heart transplant and CAV (OHT-CAV; 6 patients, 33% male, mean age 13.5years [SD 4.2]), orthotopic heart transplant without CAV (OHT; 18 patients, 67% male, mean age 11.1years [SD 4.8]), and normal healthy controls (42% male, mean age 12.8years [SD 5.0]). Transplant patients underwent cardiac catheterization with coronary angiography within 3months of echocardiogram. Post-processing of echocardiograms with speckle-tracking echocardiography and derivation of GMW indices was performed. OHT-CAV patients had decreased global work efficiency (GWE) compared to OHT (mean difference = 7.01 [1.76, 12.25], adjusted p < 0.01). LV global longitudinal strain (GLS) and LV ejection fraction were not different between groups. Both global work index and GWE were decreased in OHT-CAV and OHT when compared to normal controls (OHT-CAV 1311.23mmHg% vs OHT 1426.22mmHg% vs controls 1802.81mmHg%, adjusted p < 0.01; OHT-CAV 83.87% vs. OHT 90.87% vs. controls 95.41%, adjusted p < 0.01). GWE correlated negatively with the presence of CAV (r = - 0.44 [- 0.72, - 0.05]). This pilot study demonstrates decreased GWE correlates with pediatric CAV. This supports the need for further investigation of this promising diagnostic tool.

Nanodelivery of Mycophenolate Mofetil to the Organ Improves Transplant Vasculopathy.

Inflammation occurring within the transplanted organ from the time of harvest is an important stimulus of early alloimmune reactivity and promotes chronic allograft rejection. Chronic immune-mediated injury remains the primary obstacle to the long-term success of organ transplantation. However, organ transplantation represents a rare clinical setting in which the organ is accessible ex vivo, providing an opportunity to use nanotechnology to deliver therapeutics directly to the graft. This approach facilitates the directed delivery of immunosuppressive agents (ISA) to target local pathogenic immune responses prior to the transplantation. Here, we have developed a system of direct delivery and sustained release of mycophenolate mofetil (MMF) to treat the donor organ prior to transplantation. Perfusion of a donor mouse heart with MMF-loaded PEG-PLGA nanoparticles (MMF-NPs) prior to transplantation abrogated cardiac transplant vasculopathy by suppressing intragraft pro-inflammatory cytokines and chemokines. Our findings demonstrate that ex vivo delivery of an ISA to donor organs using a nanocarrier can serve as a clinically feasible approach to reduce transplant immunity.

Initial Intravascular Ultrasound Without a Routine Early Baseline Study in the Evaluation of Cardiac Transplant Vasculopathy has Prognostic Valve.

Abnormal minimal intimal thickening (MIT) on intravascular ultrasound (IVUS) defined as difference of ≥0.5 mm between baseline and one-year post-transplantation has been shown to have prognostic value. The goal of this retrospective cohort study was to evaluate whether abnormal MIT found on routine IVUS studies in cardiac transplant patients after 6 months without an early baseline study (modified MIT or MMIT), has any prognostic value. Furthermore, we evaluated the prognostic effect of serial IVUS performed beyond one year. A cohort of 149 cardiac transplant patients who underwent IVUS examination > 6 months post-transplant were evaluated retrospectively. Of these 149 patients, 109 patients underwent a subsequent IVUS study approximately 1 year following the initial study. MMIT values of ≥0.5 mm without an early baseline study were correlated with major adverse cardiac event (MACE). The all-cause mortality was 4.7% (5/107) in patients with MMIT of <0.5 mm vs. 14.6% (6/41) in patients with MMIT of ≥0.5 mm [hazards ratio (HR): 3.2; 95% confidence interval (CI): 1.002-12.17; p = 0.039]. The overall MACE rate was 8.4% (9/107) in patients with MMIT of <0.5 mm vs. 24.4% (10/41) in patients with MMIT of ≥0.5 mm [HR: 6.7; 95% CI: 1.30-9.42; p = 0.009]. After adjusting for age, abnormal MMIT remained a significant independent predictor of MACE (HR: 3.93; CI 1.21-12.81; p = 0.023). The presence of abnormal MMIT noted on IVUS performed after 6 months post-transplantation without a routine baseline IVUS carries important prognostic value.

Heart transplantation from older donors

In the current situation of the shortage of suitable donor organs, heart transplantation from older donors is one of the ways to increase the performance of more heart transplants, particularly, in patients with urgent need of transplantation. While planning a heart transplantation from older donor one should consider increased risk of early cardiac allograft dysfunction, preexisting coronary artery disease, accelerated transplant vasculopathy which may adversely affect early and long-term survival of recipients. Subject to careful selection of donor–recipient pairs, effective prevention and treatment of early cardiac allograft dysfunction, pre-existing atherosclerosis and transplant vasculopathy the early and long-term survival of heart transplant recipients from older donors is comparable to heart transplantation from young donors.

Eligibility and Disqualification Recommendations for Competitive Athletes with Cardiovascular Abnormalities: Task Force 8: Coronary Artery Disease: A Scientific Statement from the American Heart Association and American College of Cardiology.

Atherosclerotic coronary artery disease (ASCAD) is the leading cause of sudden cardiac death (SCD) and acute myocardial infarction (AMI) in adult athletes, variously defined as people older than age 30, 35, or 40 years.1 ASCAD can occur in younger athletes who have inherited hyperlipidemia. For many adults, SCD or AMI is the first manifestation of ASCAD, because most of these acute events are caused by coronary plaque disruption and acute coronary thrombosis in plaques that were previously not sufficiently narrowed to have caused ischemia, even during intense exercise.1 There is universal agreement that vigorous exercise, such as athletic competition, acutely, albeit transiently, increases the risk of SCD and AMI in previously healthy people.1 Vigorous exercise also transiently increases the risk for SCD and AMI in people with diagnosed ASCAD. These events may be caused by plaque disruption, but SCD in these patients may also be produced by malignant arrhythmias caused by demand ischemia or originating in areas of myocardial scar.1 In addition to ASCAD, other coronary conditions such as coronary vasospasm, myocardial bridging, and coronary dissection, as well as infection such as Kawasaki disease, vasculitis, and cardiac transplant vasculopathy, may also cause acute cardiac events during exercise. The present section makes recommendations on how to evaluate patients with disease of the coronary arteries and make appropriate recommendations for athletic competition. Anomalous coronary arteries are considered in the Task Force 4 report.2 We searched PubMed for English language articles reporting exercise-related issues related to coronary diseases. This search produced no clinical trials examining how competitive athletes with coronary artery diseases should be advised regarding vigorous exercise in general or athletic competition in particular. Consequently, the following recommendations are based on case series, case reports, and consensus among the committee members. Patients with ASCAD can be divided …

Prognostic value of multislice computed tomography coronary angiography (CTCA) in cardiac transplant vasculopathy

Prognostic value of multislice computed tomography coronary angiography (CTCA) in cardiac transplant vasculopathy

Myocardial infarction in an adult with cystic fibrosis and heart and lung transplant

We present a case of myocardial infarction in a 19 year old female with cystic fibrosis who had a heart and lung transplant performed at the age of four years old. She presented atypically with a one day history of severe, intermittent, central, sharp chest pain, radiating to her back and down her left arm. A coronary angiogram showed proximal stenosis of the left anterior descending artery and right coronary artery. She was treated with percutaneous coronary intervention, involving drug eluting stents to the left anterior descending artery (LAD) and the right coronary artery (RCA). In this study we discuss the pathophysiology, investigations and treatment of cardiac transplant vasculopathy. Although complete reversal of LAD and RCA stenosis was achieved, routine follow-up with coronary angiography and careful control of cardiac risk factors will be important to identify and reduce future restenosis and adverse cardiac events.

Myocardial infarction in an adult with cystic fibrosis and heart and lung transplant

We present a case of myocardial infarction in a 19 year old female with cystic fibrosis who had a heart and lung transplant performed at the age of four years old. She presented atypically with a one day history of severe, intermittent, central, sharp chest pain, radiating to her back and down her left arm. A coronary angiogram showed proximal stenosis of the left anterior descending artery and right coronary artery. She was treated with percutaneous coronary intervention, involving drug eluting stents to the left anterior descending artery (LAD) and the right coronary artery (RCA). In this study we discuss the pathophysiology, investigations and treatment of cardiac transplant vasculopathy. Although complete reversal of LAD and RCA stenosis was achieved, routine followup with coronary angiography and careful control of cardiac risk factors will be important to identify and reduce future restenosis and adverse cardiac events.

Non-HLA Antibodies Targeting G-Protein Coupled Receptors Induce mTORC1 and mTORC2 Signalling in Human Microvascular Endothelium

Functional non-HLA antibodies targeting G protein-coupled receptors (GPCR) Angiotensin II Type 1 receptor (AT1R) and Endothelin-1 Type A receptor (ETAR) are implicated in pathogenesis of renal and cardiac transplant vasculopathy. Both antibodies activate canonic G-protein related ERK 1/2. While Erk-signaling may represent general cellular response to agonist stimulation, the molecular link between receptor stimulation and development of vascular obliterative lesion has not been fully established yet. We hypothesized the involvement of PI3K/Akt downstream signalling target mammalian target of rapamycin (mTOR) and assessed the relative importance of the two different signalling complexes mTORC1 and mTORC 2. Human microvascular endothelial cells (hMEC) with reliable expression of target antigens were stimulated with AT1R-Ab and ETAR-Ab containing IgG from patients with obliterative vasculopathy. Phospho-specific antibodies directed against mTOR downstream targets was used to assess activation of mTORC1 (pp70S6K at Thr389) and mTORC2 (pAkt at Ser473). Signalling activity of both, mTORC1 and mTORC2, was increased after short-term treatment with patient IgG compared to cells treated with IgG from healthy controls. This effect could be inhibited by preincubating the cells with specific blockers of the AT1R (Valsartan) and ETAR (Sitaxentan). Phosphorylation of p70S6K as well as of pAkt at Ser473 was completely abolished by the pharmacologic mTOR inhibitor. Additional experiments demonstrated an ERK 1/2 independent activation of both mTOR complexes indicating a direct activation via PI3K/Akt. We provide evidence that functional non-HLA antibodies targeting AT1R and ETAR induce mTORC1 and mTORC2 signalling which is independent of canonic ERK 1/2 activation in human microvascular endothelium. Our data may provide a translational rationale for therapeutic mTOR inhibition in patients with non-HLA antibodies.

Drug‐eluting stent implantation for the treatment of cardiac transplant vasculopathy: The jury is still out

Drug‐eluting stent implantation for the treatment of cardiac transplant vasculopathy: The jury is still out

Utilization of serial intravascular ultrasound in the evaluation of cardiac transplant vasculopathy

Introduction: Coronary artery disease (CAD) is the leading cause of morbidity and mortality in diabetic patients. It is unclear whether the coronary atherosclerotic plaque burden is similar in diabetics as in the general population. The aim of the study was to assess the differences in the presence, extent, and composition of coronary atherosclerotic plaque burden as detected by multislice computed tomography coronary angiography (MSCTA) in diabetic patients as compared to those with no diabetes. Methods: A total of 150 consecutive patients of whom 69 (46%) were diabetics underwent MSCTA. Study patients were classified as having no CAD, mild-moderate CAD (b50% stenosis), or moderate-severe CAD (N50% stenosis). Plaques were classified as calcific, noncalcific (mixed), or soft. Finally, patients were classified as having no CAD, having singlevessel CAD, and having more than one vessel CAD. Results: Diabetics less frequently had a normal MSCTA (36.2% vs. 59.3%, P=.008) and more frequently had obstructive plaques (43.5% vs. 18.5, P=.002). They had more calcific (0.83±1.2 vs. 0.28±0.71, P=.004) and noncalcific plaques (0.55±0.88 vs. 0.29±0.52, P=.048) and had more coronary arteries diseased (1.9±1.8 vs. 0.99±1.6, P=.001). Diabetes correlated with number of obstructive plaques (CI=1.6–7.1, P=.001), number of calcified plaques (CI=0.87–0.54, P=.001), and presence of multivessel disease (CI=2.41–10.27, P=.001). Conclusion: Diabetics have an overall increased coronary atherosclerotic plaque burden with approximately fourfold higher risk of coronary stenosis independent of other cardiovascular risk factors and a ninefold higher risk of multivessel CAD independent of other cardiovascular risk factors. Thus, MSCTmay be used to identify differences in coronary plaque burden, which may be useful for risk stratification. Abstracts / Cardiovascular Revascu

Progression of Coronary Atherosclerosis After Heart Transplantation on Electron-beam Computed Tomography

Cardiac transplant vasculopathy is the most important long-term complication of heart transplantation, with overlapping features with conventional, atherosclerotic coronary artery disease. The aim of this study was to determine the progression of coronary artery disease after heart transplantation by measuring total coronary calcium load. After heart transplantation, 185 patients were serially examined using electron-beam computed tomography for coronary calcium load for clinical reasons. The mean time between the initial examination and the follow-up scan was 566 days (range, 126-1,436). Coronary calcium load was measured by the Agatston method, and the total calcium scores at both examinations were compared between patients taking and those not taking lipid-lowering medications (statins). Patients not taking statins (n = 94) displayed a median annualized percentage increase in total calcium score of 0 Agatston units, whereas patients taking at least the lowest recommended daily dose of a statin (n = 84) displayed an annualized percentage decrease of 11 Agatston units. The difference was not statistically significant (Wilcoxon's rank-sum test, P = .35). Only 17 patients had increases of > 24 Agatston units, and eight of them were taking statins (chi(2) test, P = .99). The annual rate of progression of coronary calcium load after heart transplantation is low. In this investigation, no beneficial effects of statins could be detected.

The Role of Multiple Drug-Eluting Stents in the Treatment of Cardiac Transplant Vasculopathy

A 60-year-old male with cardiac transplantation six years prior was seen for easy fatigability and dyspnea on exertion. Electrocardiogram revealed new T-wave inversions in the anterolateral leads. Cardiac catheterization showed diffuse multivessel disease with significant stenosis consistent with cardiac transplant vasculopathy (CTV). Percutaneous intervention was performed with DES with improvement of symptoms. Follow-up cardiac catheterization revealed patent stents. CTV is the most common cause of death in heart transplant patients. Due to denervated heart, these patients rarely experience chest pain. Revascularization options are limited given the diffuse nature of the disease. Due to their very low restenosis rates, DES may represent a viable alternative to retransplantation.

The Role of Drug-Eluting Stents in Treating Cardiac Transplant Vasculopathy

The Role of Drug-Eluting Stents in Treating Cardiac Transplant Vasculopathy

Drug-eluting stents for the treatment of coronary lesions in cardiac transplant vasculopathy: acute and mid-term clinical and angiographic outcomes

Cardiac allograft vasculopathy (CAV) is the major cause of graft failure and death in cardiac transplant recipients after transplantation. We aimed to evaluate the clinical and angiographic outcomes of patients with evidence of CAV who were treated percutaneously with drug-eluting stents (DES-PCI). Between December 2002 and September 2005, we reviewed the baseline procedural characteristics and the clinical outcome of consecutive cardiac transplanted recipients with evidence of CAV treated with DES-PCI, eligible for at least 9 months of follow-up. Fifteen consecutive patients received a total of 18 coronary DESs. Total treated lesions were 20; 12 (60%) involved the left anterior descending artery. CAV was focal in nine patients, diffuse in five patients, and mixed in only one patient. Mean time interval from transplantation to DES implantation was 126 +/- 44 months. Angiographic and procedural success was 100%. There were no adverse in-hospital events. During follow-up (17.9 +/- 8.4 months), two patients died of noncardiac cause. Six patients required a new percutaneous intervention for a repeat revascularization rate of 40%: one patient underwent target lesion revascularization because of in-DES restenosis, one patient had target vessel revascularization because of a new coronary lesion proximal to the stent. Finally, four more patients underwent repeat DES-PCI in a coronary vessel other than the treated one. Although DES implantation seems to be associated with a high procedural success rate and a low restenosis rate, the repeat revascularization rate due to CAV progression remains in nearly half of our study patients.

Heart transplantation: a magnified model of heart-brain interactions.

The human heart transplant model unmasks the heart-brain link as an active process that is clinically demonstrated and confirmed at the tissue level. Further studies are needed to elucidate the relative contribution of each of these isolated observations to the pathogenesis of coronary allograft vasculopathy, which remains enigmatic. Recent studies have suggested that mTOR inhibitors may have the ability to attenuate this lethal process that limits the long-term survival of cardiac transplant recipients. The observations we have discussed here suggest that other targeted therapies, including glycoprotein IIb/IIIa inhibitors, tissue metalloproteinase inhibitors, and angiotensin receptor blockers, may facilitate the attenuation of cardiac transplant vasculopathy, but clinical trials are difficult to conduct in this relatively small population of patients. These observations may shed insight, however, into the pathophysiology of hypertension and its impact on the vascular system, as cardiac transplantation provides a setting in which heart-brain interactions are magnified and the pathophysiology occurs over years rather than decades.

In-Stent Restenosis and Remote Coronary Lesion Progression Are Coupled in Cardiac Transplant Vasculopathy But Not in Native Coronary Artery Disease

The purpose of this study was to describe the clinical, angiographic, and histological features of concomitant in-stent restenosis (ISR) and cardiac allograft vasculopathy (CAV) progression. Cardiac allograft vasculopathy is a major challenge to long-term success of heart transplantation. Coronary stenting for CAV is hampered by ISR. Quantitative coronary angiography compared late lumen loss (LL) at stented and reference, non-stented segments during 1-year follow-up in post-heart transplant and control atherosclerosis patients. Stented and non-stented arteries with CAV were also obtained post-mortem for immunohistochemical analysis. In 37 stented lesions (25 patients), 1-year binary restenosis occurred in 37.8%. Patients with ISR had higher long-term cardiac death/myocardial infarction rates than patients without ISR (53.8% vs. 9.1%, p = 0.03). In the same 25 patients, 34 CAV lesions with non-significant obstructions were identified as reference controls. After 1 year, patients who developed ISR also had more control lesion LL (0.78 +/- 0.38 mm vs. 0.39 +/- 0.27 mm, p < 0.006) compared to patients without ISR. In the post-transplant patients, in-stent LL was closely coupled to control segment LL (R(2) = 0.63, p < 0.05). Conversely, in native atherosclerosis patients, ISR and remote disease progression were not correlated. Histological staining of stented and control arteries from CAV patients revealed similar pathologies common to ISR and non-intervened CAV segments. Progression of CAV at non-intervened segments and ISR correlate strongly and share common histopathology. Optimized treatment for patients with aggressive CAV needs to address the widespread nature of this disease, even when it presents as an initially focal lesion.

Usefulness and Safety of Percutaneous Coronary Interventions for Cardiac Transplant Vasculopathy

Late morbidity and death as a result of progressive coronary vascular obliteration remains a major unsolved problem after orthotopic heart transplantation. Various percutaneous catheter intervention (PCI) methods have been used to treat transplant coronary artery disease (CAD), but few reports have assessed the longitudinal results of these procedures. Of 1,440 cardiac transplant patients at University of California, Los Angeles, Medical Center, treated between 1984 and 2004, 65 patients who had undergone orthotopic heart transplantation underwent PCI on a total of 156 coronary artery lesions because of transplant CAD between July 1993 and August 2004. The procedural success rate was 93%. Angiographic follow-up was available for 42 patients and 101 lesions 9.5 +/- 5.8 months after PCI. The global restenosis rate was 36%. Multivariate analysis was used to assess 49 clinical, angiographic, and immunologic variables per lesion. The use of a cutting balloon increased the risk of restenosis (odds ratio 11.5, p <0.01) and the use of stents decreased the risk of restenosis (odds ratio 0.34, p <0.05) compared with other PCI methods. The restenosis rate with drug-eluting stents was 19%, lower than that with bare metal stents (31%). Of the 65 patients, 20 (31%) died within 1.9 +/- 1.8 years after PCI. The actuarial survival rate was 56% at 5 years after the first PCI. In conclusion, although the restenosis rate after PCI was higher than that in nontransplant patients with CAD, the immediate and long-term results were acceptable in this high-risk population. Despite the intense inflammation associated with transplant CAD, drug-eluting stents appeared to reduce the occurrence of restenosis. Compared with historical controls, PCI may also improve the actuarial survival rate of patients undergoing orthotopic heart transplantation.

Haptoglobin phenotype correlates with development of cardiac transplant vasculopathy

Objectives: The purpose of this study was to investigate the association between haptoglobin phenotypic variation and development of cardiac transplant vasculopathy. Background The development of coronary vasculopathy determines long-term survival after cardiac transplantation. Serum haptoglobin levels are associated with non-transplant atherosclerosis. In addition to free hemoglobin binding, haptoglobin influences free radical formation, prostaglandin synthesis and angiogenesis. Three phenotypes of haptoglobin exist in humans, which have both quantitative and qualitative differences. Methods Coronary disease was diagnosed at post-transplant routine surveillance angiography. Hemoglobin (10%) was added to recipient plasma to form a haptoglobin-hemoglobin complex. Sample aliquots were applied to acid hemoglobin plates and electrophoretically separated. Phenotypes were recognized by comparing the electrophoretic pattern with that of established standards. Haptoglobin concentrations were measured using an immunoturbidimetric technique with polyethylene glycol (PEG)-enhanced precipitation. Results Ninety-three patients were independently studied. Phenotype 1-1 was found in 20.4%, 2-1 in 41.9% and 2-2 in 37.6%. Haptoglobin levels were highest in 1-1 recipients (2.1 ± 0.58 g/liter) compared with 1.78 ± 0.88 g/liter and 1.3 ± 0.81 g/liter in 2-1 and 2-2 individuals, respectively ( p = 0.001). Haptoglobin phenotype was significantly related to the development of vasculopathy; recipients with a 2-1 phenotype were more likely to develop angiographic disease ( p = 0.0084). No differences were found among the 3 groups according to univariate analysis. Multivariate analysis identified 3 risk factors for vasculopathy development: age of donor (hazard ratio 1.056 [95% confidence interval 1.02 to 1.094], p = 0.0023); pre-transplant recipient body mass index (hazard ratio 1.116 [95% confidence interval 1.015 to 1.23], p = 0.024), and haptoglobin phenotype (hazard ratio 2.725 [95% confidence interval 1.031 to 7.19], p = 0.012). Conclusions Haptoglobin, through phenotype-dependent mechanisms, correlates with the development of coronary vasculopathy. This finding furthers our understanding of the disease, opens up new areas of research, and may lead to novel therapies.

Value of circulating adhesion molecules in assessing cardiac allograft vasculopathy

Circulating adhesion molecules have been implicated in the development of spontaneous and transplant coronary artery disease. We analyzed soluble (s) intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1), and sE-selectin levels from the coronary sinuses of 25 cardiac allograft recipients, and we correlated these molecules with the degree of acute rejection detected in endomyocardial biopsy specimens and the presence of transplant vasculopathy assessed with coronary angiography. We found that sVCAM-1 significantly increased in patients with transplant vasculopathy compared with those without transplant vasculopathy, whereas sE-selectin and sICAM-1 did not. Therefore, increased coronary sinus levels of sVCAM-1 is a reliable marker in assessing cardiac transplant vasculopathy.