Allograft Coronary Disease Research Articles

Outcomes of Mechanical Circulatory Support Therapy for Cardiogenic Shock Associated with Late Allograft Failure after Heart Transplantation

Treatment of cardiogenic shock associated with late allograft failure after heart transplant (HT) is poorly characterized and infrequently reported. In this study, we examined the role of mechanical circulatory support (MCS) as a method to treat patients with severe late graft failure. From 2000 - 2018, there were 1275 adult HT at our institution. Of those, 26 patients (2.0%) were identified who required MCS for cardiogenic shock due to late allograft failure. Patient demographics and outcomes were retrospectively reviewed. Median age of the cohort was 37.3 years (IQR: 17.3) and 69% were male. Median time from initial transplant to MCS was 2.9 years. At the time of shock, median hemodynamic values were as follows: CVP 18 mmHg, mean PA pressure 29 mmHg, PCWP 25 mmHg, and CI 1.87 L/min/m2. On echocardiogram, median LVEF was 25% and 77% of patients had moderate or severe right ventricular dysfunction. Seven patients (27%) had severe allograft coronary disease, while all remaining patients had chronic or acute worsening rejection. Initial MCS used included veno-arterial extracorporeal membrane oxygenation in 15 patients (58%), biventricular assist device in 10 patients (38%), and total artificial heart in 1 patient (4%). 8 patients underwent revision of MCS during the same hospitalization, on average 18 days after initial placement. While on MCS, the most common treatments for rejection were pulse dose steroids (69%), thymoglobulin (54%), and plasmapheresis (31%), with nearly all patients receiving combination therapy. Six patients (23%) weaned from MCS following medical therapy. Median duration of MCS was 33 days (IQR 55). Major morbidities included bleeding events in 39%, new renal replacement therapy in 23%, major infection in 27%, and stroke in 23%. Eight patients (31%) underwent re-heart transplant, all within one year of MCS, and survival for this cohort was 100% at 1 year. However, for those patients who were not offered re-transplant or who died while awaiting re-transplant, 1 year survival was only 22%, with 61% of deaths occurring in the hospital. Late graft failure resulting in cardiogenic shock carries significant morbidity and mortality, despite use of contemporary MCS.

Total Lymphoid Irradiation in Heart Transplantation: Long-Term Efficacy and Survival—An 18-Year Experience

Total lymphoid irradiation (TLI) has been used in transplantation for over 20 years and is currently used in a number of major heart transplant centers as a secondary therapy for recalcitrant recurrent rejection or rejection with hemodynamic compromise. The purpose of this study is to evaluate the long-term risks and efficacy of TLI in the treatment of rejection. Between 1990 and 1996, 73 adult patients (from 211 adult transplant recipients) received TLI for recurrent rejection (71%), rejection with hemodynamic compromise (25%), and rejection with vasculitis (4%). The treatment consisted of 80 cGy twice per week for 5 weeks. Fifty-five patients received at least 80% of the full dose (>640 cGy). Follow-up ended December 31, 2007, comprising a total 18 year experience. Patients treated with TLI exhibited a short-term decrease in hazard for rejection in the first 12 months posttransplantation (relative risk, 0.36) but exhibited increased cumulative rejection over the long term. There were no differences in the rates of infection, allograft coronary disease, or malignancy, but seven patients developed myelodysplasia or acute myelogenous leukemia, four of those being the rare but uniformly fatal acute megakaryocytic leukemia type 7. Patients treated with TLI seemed to experience a reduction in the early hazard for rejection, but long-term outcomes indicate that such patients continued to accumulate more rejection and rejection-death events, likely because these patients were overall at much higher risk for rejection than the other patient groups. We observed minimal long-term complications, except for the unique occurrence of myelodysplasia and acute megakaryocytic leukemia type 7.

Contribution of Recipient-Derived Cells in Allograft Neointima Formation and the Response to Stent Implantation

Allograft coronary disease is the dominant cause of increased risk of death after cardiac transplantation. While the percutaneous insertion of stents is the most efficacious revascularization strategy for allograft coronary disease there is a high incidence of stent renarrowing. We developed a novel rabbit model of sex-mismatched allograft vascular disease as well as the response to stent implantation. In situ hybridization for the Y-chromosome was employed to detect male cells in the neointima of stented allograft, and the population of recipient derived neointimal cells was measured by quantitative polymerase chain reaction and characterized by immunohistochemistry. To demonstrate the participation of circulatory derived cells in stent neointima formation we infused ex vivo labeled peripheral blood mononuclear cells into native rabbit carotid arteries immediately after stenting. Fourteen days after stenting the neointima area was 58% greater in the stented vs. non-stented allograft segments (p = 0.02). Male cells were detected in the neointima of stented female-to-male allografts. Recipient-derived cells constituted 72.1±5.7% and 81.5±4.2% of neointimal cell population in the non-stented and stented segments, respectively and the corresponding proliferation rates were only 2.7±0.5% and 2.3±0.2%. Some of the recipient-derived neointimal cells were of endothelial lineage. The ex vivo tagged cells constituted 9.0±0.4% of the cells per high power field in the stent neointima 14 days after stenting. These experiments provide important quantitative data regarding the degree to which host-derived blood-borne cells contribute to neointima formation in allograft vasculopathy and the early response to stent implantation.

383: Relationship between u-PA and TGF genotype and allograft coronary disease

Purpose: Cytokines and fibrinolytic proteins are involved in the development of allograft coronary disease (ACD) and polymorphisms in respective genes may affect their expression. We analyzed the role of TGF-β allelic variation in codon 25 and polymorphisms in u-PA to determine the risk of ACD in cardiac transplant recipients (CTx).

Of Mice and Men: Mouse Models and the Molecular Mechanisms of Post-transplant Coronary Artery Disease

m he threat posed to cardiac transplant recipients by the evelopment of post-transplant allograft coronary arery disease (ACD) is widely recognized. Multi-instituional outcomes studies show that ACD is the primary ause of death in approximately 22% of patients who ie 1 to 3 years post-transplantation. The proportion ncreases to as high as 29% beyond 3 years postransplantation. Yet, of all the major post-transplant henomena that adversely affect the outcome of cariac transplantation, ACD is arguably the most poorly nderstood. This is especially apparent when compared ith the rapid rate at which the understanding of ascular disease in the general population (i.e., “native” therosclerosis) has proceeded in recent years. In large part, this lag in understanding is due to the ncreased complexity of post-transplant disease, in hich established mechanisms of native atherosclerosis re overlaid by alloimmune responses of the recipient irected toward the donor organ. An additional imporant reason is that native atherosclerosis research has een facilitated by the development of a consensus round a relatively small number of standard animal odels, whereas no integrated hypothetical model has ppeared that incorporates the wide array of experiental systems used for the study of ACD. This review has 2 objectives. The first is to discuss he relative differences in current murine experimental ystems and the impact of these differences on the nterpretation of the data generated by them. The econd is to present a unified theoretical model of ACD. ecause of the paucity of data that directly address the echanisms of ACD, elements of the model presented ere are necessarily speculative since some evidence sed for building it must be drawn from experimental odels of other inflammatory diseases. Therefore, until

Angiographic, Pathologic, and Clinical Relationships in Coronary Artery Disease in Cardiac Allografts

To date, the etiologic factors involved in the development of allograft coronary disease remain speculative and the treatment uncertain. The purpose of this study was to review the relationship of clinical, angiographic, and pathologic features of cardiac allograft vascular disease in a large population of heart transplant recipients followed for up to 15 years. From 1981 to 1996, 789 angiograms from 255 cardiac allografts were reviewed to determine the prevalence and severity of coronary artery disease. Demographic, clinical, and laboratory variables were analyzed to identify factors associated with the presence of angiographic coronary artery disease. In addition, pathologic examination was performed on many of the lost grafts. Unsuspected severe donor coronary artery disease may be responsible for up to 10% of early graft failures. Angiographic coronary artery disease prevalence increased by approximately 10% with every 2-year interval after transplantation. Angiographic coronary artery disease consisted most often of minor luminal irregularities. Severe disease occurred in 12% of patients. At 1 year, the most significant factors associated with the presence of coronary artery disease were older donor age and the number of rejection episodes. Immunologic factors as well as traditional coronary risk factors such as hypercholesterolemia and hyperglycemia may play an important role in the genesis and progression of later-developing abnormalities. Cardiac allograft coronary artery disease is a major limiting factor to the long-term success of cardiac transplantation. Immune processes, as well as traditional coronary artery disease risk factors, appear to play a role in the development of this disease.

Is biopsy-proven cellular rejection an important clinical consideration in heart transplantation?

Immunosuppression strategies to prevent allograft rejection represent the cornerstone of long-term survival after heart transplantation. Endomyocardial biopsy has defined rejection in clinical cardiac transplantation and established a threshold for therapy. With the development of more effective immunosuppression modalities and the asymptomatic nature of most histologic rejection episodes, controversy exists regarding the need to augment immunosuppression based purely on histologic findings. The frequency of histologic rejection has declined with current immunosuppression. Resolution of lower grades of histologic rejection without treatment is the norm in both pediatric and adult heart transplant studies. Recurrent rejection episodes have been linked to the subsequent development of allograft coronary artery disease, and late rejection (even if asymptomatic) is associated with decreased survival in pediatric heart transplant recipients. Black race is a risk factor for recurrent rejection and reduced survival after late cellular rejection. Apoptosis of inflammatory cells is more evident during and after histologic rejection treated with corticosteroids. Despite numerous noninvasive modalities evaluated for the detection of rejection, to date noninvasive methods cannot reliably predict histologic rejection. Histologic rejection appears less common with current immunosuppressive strategies, and controversy exists about the need to treat asymptomatic rejection. It remains unproven whether non-treatment of moderate or greater rejection (>/=3A) increases the likelihood of recurrent rejection, which if present, may increase the risk of allograft coronary disease and/or reduced long-term survival.

Palliation of allograft vasculopathy with transluminal angioplasty: A decade of experience

ObjectivesThe goal of this study was to examine the outcomes of percutaneous coronary interventions (PCI) and the predictors for restenosis after cardiac transplantation. BackgroundThe role of PCI as definitive therapy for allograft coronary disease (ACD) remains contentious. MethodsBetween January 1, 1990 and December 31, 2000, 62 patients (1.5 to 15.5 years after transplant) underwent 151 procedures resulting in PCIs of 219 lesions. Follow-up after PCI angiography was usually obtained at three and six months, then yearly. Repeat PCI was routinely done to lesions with >60% restenosis. ResultsThe primary procedural success was 97%. Repeat PCI occurred in 74 of 219 lesions (34%); PCI-related mortality was 2.6% (4 of 151). The freedom from re-PCI (of same vessel site) was 75% at six months, 65% at one year, and 57% at four years. The freedom from restenosis was 95% at one month, 81% at three months, and 57% at six months. Multivariate predictors of freedom from restenosis were the use of stents, higher anti-proliferative immunosuppressant dose, and an era effect. In the setting of one-vessel disease at first PCI, the two-year freedom for ACD death or graft loss was 74%, compared with 75% for two-vessel and 27% for three-vessel disease (p = 0.009). ConclusionsDespite the increasing effectiveness of PCI for localized ACD, the survival after development of advanced ACD remains poor. Stents appear to increase effectiveness of PCI for ACD, but other factors in the current era contribute to improved outcomes.

Non-invasive screening by tissue doppler for late post-transplant cardiac rejection surveillance

Routine endomyocardial biopsies (EMBs) continue to detect acute cardiac rejection (AR) beyond the first post-transplant year, but their need for late AR surveillance is controversial. However, late ARs are linked to both graft failure and allograft coronary disease (ACD). To provide appropriate AR surveillance during late post-transplant periods, we assessed the value of tissue Doppler imaging (TDI) screening for both AR diagnosis and effective use of EMBs.

Strategies for minimizing hyperlipidemia after cardiac transplantation.

Allograft coronary artery disease represents a major limitation to long-term survival after cardiac transplantation. Hyperlipidemias have been linked to the development of native coronary atherosclerosis, and hyperlipidemic states have correlated with the severity of allograft coronary artery disease. Heart transplant recipients typically manifest increases in plasma levels of total cholesterol, low-density lipoprotein-cholesterol (LDL-C), and triglycerides within the first 3-12 months following transplantation. Factors known to promote post-transplant hyperlipidemia include the use of corticosteroids, cyclosporine (interference with clearance and increased oxidizability of LDL), sirolimus (hypertriglyceridemia), and patient-specific causes of hyperlipidemia which contributed to their underlying heart disease. Hydroxymethylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors are the foundation of antilipid therapy following cardiac transplantation. Pravastatin is effective in lowering plasma cholesterol levels and is associated with a decreased incidence and progression of allograft coronary artery disease. All HMG-CoA reductase inhibitors except pravastatin are metabolized by the hepatic cytochrome P450 system which metabolizes cyclosporine, increasing the risk of myostitis when they are used in large dosages with cyclosporine. Simvastatin, atorvastatin and fluvastatin have been studied in heart transplant recipients. Gemfibrozil has proved effective in transplant recipients when there is isolated marked elevation of plasma triglyceride levels. When hyperlipidemia persists despite therapy, some benefit may result with conversion from cyclosporine to tacrolimus. Although a definitive link between hyperlipidemia and allograft coronary disease has yet to be proven, available evidence points to abnormal lipid metabolism as part of the complex etiologic machinery driving the process of 'chronic rejection'. Consensus exists within the transplant community that a HMG-CoA reductase inhibitor such as pravastatin, should be part of the routine post-transplant drug regimen, and persistent hyperlipidemia should be aggressively treated.

Alterations in the fibrinolytic cascade: implications for allograft coronary disease

Perturbations in the fibrinolytic cascade after cardiac transplantation (CTx) may affect the development of allograft coronary disease (ACD). Currently, little is known about time-related changes in the components of this system. The early results of an NIH-sponsored trial were analyzed to evaluate these issues.

Mild cardiac allograft coronary disease does not change the prognosis of patients after heart transplantation

Mild cardiac allograft coronary disease does not change the prognosis of patients after heart transplantation

Prognosis of patients with significant angiographically diagnosed cardiac allograft coronary disease

Prognosis of patients with significant angiographically diagnosed cardiac allograft coronary disease

Mild hyperhomocysteinemia is not associated with cardiac allograft coronary disease.

Hyperhomocysteinemia is an independent risk factor for coronary disease and elevated plasma homocysteine levels have been documented in heart transplant recipients. The aim of this study was to test the hypothesis that homocysteine levels are associated with presence or absence of transplant coronary artery disease. Forty-three non-smoking adults were recruited, all of whom had received a heart transplant between 2 and 7 yr previously. All 43 had blood drawn for fasting homocysteine level on the day of presentation. All patients had undergone diagnostic coronary angiography within the past 6 months. For all patients, the average fasting plasma homocysteine level was 17.0+/-SD 6.6 micromol/L with a range from 6.0 to 36.9 micromol/L. Twenty-six patients (60%) had fasting plasma homocysteine levels above 15.0 micromol/L. On the basis of arteriography, patients were categorized as those with angiographically normal (n=22) or abnormal (n=21) coronary arteries. There was no difference in the mean plasma homocysteine level comparing patients with angiographically normal (17.2+/-SD 7.0 micromol/L) to those with abnormal (16.8+/-SD 6.2 micromol/L) coronary arteries. Plasma homocysteine levels increased with increasing plasma creatinine levels (r=0.63, p<0.0001) and with decreasing vitamin B6 levels (r=-0.56, p<0.0001). Mild hyperhomocysteinemia is a consistent finding among heart transplant recipients. This finding was not associated with transplant coronary artery disease in our patients. The combination of renal dysfunction and vitamin B6 deficiency may explain the unusual prevalence of hyperhomocysteinemia in heart transplant recipients.

Photodynamic therapy using motexafin lutetium in allograft coronary artery disease

Graft coronary artery disease (GCAD) limits long-term patient survival following heart transplantation. There are few treatment options. Exploration into less invasive diagnostic techniques and attenuation of allograft coronary disease is warranted. The selectivity of Antrin®Injection (a motexafin lutetium sensitizer, Lu-Tex) and illumination with far-red light, approximately 732 nm, has been evaluated in several preclinical atherosclerosis models. Lu-Tex, using fluorescence microscopy, was found to partition into distinct punctate cytoplasmic compartments in cultured human bypass coronary smooth muscle cells (SMCs). Using specific organelle probes the chief subcellular localization sites were lysosomes and endoplasmic reticulum. The inhibitory effect of Lu-Tex-mediated photoactivation was demonstrated using SMCs; many cells died via an apoptotic pathway. Following illumination, fluorescence microscopy revealed sensitizer redistribution with fluorescence being observed in the mitochondria. The distribution of Lu-Tex was evaluated in a rat model of heterotopic cardiac allografts 60 days after transplantation. Lu-Tex was retained in the cardiac allograft, exhibiting a five-fold increase in retention between the allograft and native heart. These results encourage further exploration of Lu-Tex for diagnosis, and possible amelioration of chronic graft vascular disease using photodynamic therapy.

Bethesda conference: conference for the design of clinical trials to study circulatory support devices for chronic heart failure

James M. Anderson, MD Eugene H. Blackstone, MD Harvey S. Boroevetz, PhD Arthur Ciarkowski, MD Jack G. Copeland III, MD Maria Rosa Costanzo-Nordin, MD Kurt Daase, MD Mary Amanda Dew, PhD Michael J. Domanski, MD Benjamin H. Eidleman, MD Roger W. Evans, PhD David J. Farrar, PhD O. H. Frazier, MD Bartley P. Griffith, MD Charles-Julien Hahn, MD J. Donald Hill, MD Sharon Hunt, MD Kay Kendell, RN Robert L. Kormos, MD Howard R. Levin, MD Donna M. Mancini, MD Patrick M. McCarthy, MD Dennis McNamara, MD Fr Kevin O’Rourke, PhD Lisa Parker, PhD D. Glenn Pennington, MD Victor L. Poirier, PhD Peer M. Portner, PhD Eric A. Rose, MD Wolf Sapirstein, MD Eleanor Schron, MD Rhona Shanker, MD Ramiah Subramanian, MD John Wallwork, MD Lynne Warner Stevenson, MD

The role of inflammation in the development of allograft coronary disease

The role of inflammation in the development of allograft coronary disease

Allograft aortopathy: An in vivo study of donor aorta involvement in cardiac allograft vasculopathy

Limited histopathologic studies of failed cardiac allografts have demonstrated that cardiac allograft vasculopathy extends into the donor aorta; however, no study has examined the development of allograft aortic intimal proliferation in vivo in conjunction with coronary intimal hyperplasia. By using simultaneous intracoronary and intraaortic ultrasound, we studied 20 consecutive heart transplant recipients at 2.5 ± 2.1 years after transplantation. The degree of coronary intimal thickening was strongly correlated with the development of intraaortic intimal hyperplasia ( r = 0.90; p < 0.0001). Multivariate predictors of aortic intimal thickening included years after transplant ( r = 0.47; p = 0.03), serum cholesterol level ( r = 0.65, p = 0.003), and serum triglyceride level ( r = 0.51; p = 0.03). Allograft aortopathy occurs in a similar manner to allograft coronary disease, thus providing support for the notion that an immunologic stimulus operating across the allograft vascular bed may be responsible for the development of cardiac allograft vasculopathy. Furthermore, this investigation provides insight into the putative role of hyperlipidemia in allograft vascular disease. (Am Heart J 1997;133:698-702.)

The need for artificial hearts.

Chronic immunosuppression, allograft coronary disease, and restricted availability of donor organs continue to limit the scope of cardiac transplantation. Meanwhile increasingly favourable experience with implantable blood pumps used as a bridge to transplant has reintroduced the concept of permanent mechanical cardiac support. Existing models (for example, the Thermo Cardiosystems Heartmate device) are now used for such support in patients who are not candidates for transplantation. Miniaturised axial flow pumps such as the Jarvik 2000 fit within the failed left ventricle and provide an exciting prospect for the treatment of heart failure in the future. Preliminary experience suggests that the "offloaded" left ventricle may recover. Mechanical blood pumps can be used before the onset of multisystem failure and removed if the myocardium recovers. This "bridge to recovery" concept should be tested in patients with recoverable cardiomyopathy and those with coronary disease and poor left ventricular function where an implantable pump can be used in conjunction with myocardial revascularisation.

Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients

This study sought to analyze the outcomes of revascularization procedures in the treatment of allograft coronary disease. Allograft vasculopathy is the main factor limiting survival of heart transplant recipients. Because no medical therapy prevents allograft atherosclerosis, and retransplantation is associated with suboptimal allograft survival, palliative coronary revascularization has been attempted. Thirteen medical centers retrospectively analyzed their complete experience with percutaneous transluminal coronary angioplasty, directional coronary atherectomy and coronary bypass graft surgery in allograft coronary disease. Sixty-six patients underwent coronary angioplasty. Angiographic success (< or = 50% residual stenosis) occurred in 153 (94%) of 162 lesions. Forty patients (61%) are alive without retransplantation at 19 +/- 14 (mean +/- SD) months after angioplasty. The consequences of failed revascularization were severe. Two patients sustained periprocedural myocardial infarction and died. Angiographic restenosis occurred in 42 (55%) of 76 lesions at 8 +/- 5 months after angioplasty. Angiographic distal arteriopathy adversely affected allograft survival. Eleven patients underwent directional coronary atherectomy. Angiographic success occurred in 9 (82%) of 11 lesions. Two periprocedural deaths occurred. Nine patients are alive without transplantation at 7 +/- 4 months after atherectomy. Bypass graft surgery was performed in 12 patients. Four patients died perioperatively. Seven patients are alive without retransplantation at 9 +/- 7 months after operation. Coronary revascularization may be an effective palliative therapy in suitable cardiac transplant recipients. Angioplasty has an acceptable survival in patients without angiographic distal arteriopathy. Because few patients underwent atherectomy and coronary bypass surgery, assessment of these procedures is limited. Angiographic distal arteriopathy is associated with decreased allograft survival in patients requiring revascularization.