Sharon Chih

A Survey of Current Practice for Antibody-Mediated Rejection in Heart Transplantation

No evidence based management guidelines exist for antibody mediated rejection (AMR) in heart transplantation. The International Society for Heart and Lung Transplantation (ISHLT) recently introduced standardized pathologic based diagnostic criteria for AMR (pAMR 0–3). We evaluated international practice for the management of AMR focusing on pAMR grade, donor specific antibody (DSA) and allograft function. On‐line survey data were analyzed from 184 ISHLT members (physicians‐78%, surgeons‐20%). The majority were from adult‐transplant (84%), medium‐large volume centres (transplants/year: 10–25, 61%; 25–50, 19%) across North America (60%) and Europe (26%). Irrespective of pAMR grade and DSA, 83–90% treated a drop in ejection fraction (EF ≤45% or >25% decrease). In the presence of stable EF, an increasing number elected treatment for progressively severe pAMR grade (p < 0.001) and for accompanying DSA (p < 0.05, pAMR 1–3). Intravenous steroid was the most commonly used therapy followed by intravenous immunoglobulin (IVIG) or plasmapheresis, rituximab and thymoglobulin. Plasmapheresis and rituximab were favored for positive versus negative DSA (p < 0.05). Using a threshold of ≥70% consensus among respondents, treatment for AMR may be considered for a drop in EF, asymptomatic pAMR 3 or asymptomatic pAMR 2 with DSA. Combination steroid, IVIG and plasmapheresis are suggested as initial therapies.

Antibody-mediated rejection: an evolving entity in heart transplantation.

Antibody-mediated rejection (AMR) is gaining increasing recognition as a major complication after heart transplantation, posing a significant risk for allograft failure, cardiac allograft vasculopathy, and poor survival. AMR results from activation of the humoral immune arm and the production of donor-specific antibodies (DSA) that bind to the cardiac allograft causing myocardial injury predominantly through complement activation. The diagnosis of AMR has evolved from a clinical diagnosis involving allograft dysfunction and the presence of DSA to a primarily pathologic diagnosis based on histopathology and immunopathology. Treatment for AMR is multifaceted, targeting inhibition of the humoral immune system at different levels with emerging agents including proteasome and complement inhibitors showing particular promise. While there have been significant advances in our current understanding of the pathogenesis, diagnosis, and treatment of AMR, further research is required to determine optimal diagnostic tools, therapeutic agents, and timing of treatment.

Reproducibility of adenosine stress cardiovascular magnetic resonance in multi-vessel symptomatic coronary artery disease

PurposeFirst-pass perfusion cardiovascular magnetic resonance (CMR) is increasingly being utilized in both clinical practice and research. However, the reproducibility of this technique remains incompletely evaluated, particularly in patients with severe coronary artery disease (CAD). The purpose of this study was to determine the inter-study reproducibility of adenosine stress CMR in patients with symptomatic multi-vessel CAD and those at low risk for CAD.MethodsTwenty patients (10 with CAD, 10 low risk CAD) underwent two CMR scans 8 ± 2 days apart. Basal, mid and apical left ventricular short axis slices were acquired using gadolinium 0.05 mmol/kg at peak stress (adenosine, 140 μ/kg/min, 4 min) and rest. Myocardial perfusion was evaluated qualitatively by assessing the number of ischemic segments, and semi-quantitatively by determining the myocardial perfusion reserve index (MPRi) using a normalized upslope method. Inter-study and observer reproducibility were assessed--the latter being defined by the coefficient of variation (CoV), which was calculated from the standard deviation of the differences of the measurements, divided by the mean. Additionally, the percentage of myocardial segments with perfect agreement and inter- and intra-observer MPRi correlation between studies, were also determined.ResultsThe CoV for the number of ischemic segments was 31% with a mean difference of -0.15 ± 0.88 segments and 91% perfect agreement between studies. MPRi was lower in patients with CAD (1.13 ± 0.21) compared to those with low risk CAD (1.59 ± 0.58), p = 0.02. The reproducibility of MPRi was 19% with no significant difference between patients with CAD and those with low risk CAD (p = 0.850). Observer reproducibility for MPRi was high: inter-observer CoV 9%, r = 0.93 and intra-observer CoV 5%, r = 0.94. For trials using perfusion CMR as an endpoint, an estimated sample size of 12 subjects would be required to detect a two-segment change in the number of ischemic segments (power 0.9, α 0.05).ConclusionsAdenosine stress CMR, by qualitative and semi-quantitative normalized upslope analyses are reproducible techniques in both patients with multi-vessel CAD and those without known CAD. The robust inter-study reproducibility of perfusion CMR supports its clinical and research application.

Successful Heart Transplant after Ten Hours Out-of-body Time using the TransMedics Organ Care System

OBJECTIVE We report the successful transplantation of a heart following an out-of-body time of 611 minutes into a recipient with dilated cardiomyopathy and left ventricular assist device implant. PATIENTS Our patient was urgently waiting for a cardiac transplant whilst receiving LVAD support. Recurrent VF and repeated AICD shocks necessitated this action. RESULTS Although requiring ECMO and inotropic support in the first 17 hours post-transplant, the patient was discharged from hospital on day 15 post-transplant with normal cardiac function. CONCLUSION We report some of the salient points of the process and discuss the utility of this technology to an Australian transplant unit.

Factors associated with anti-human leukocyte antigen antibodies in patients supported with continuous-flow devices and effect on probability of transplant and post-transplant outcomes

BACKGROUND One major disadvantage of ventricular assist device (VAD) therapy is the development of human-leukocyte antigen (HLA) antibodies. We aimed to identify factors associated with HLA antibodies during continuous flow (CF)-VAD support and assess the effect on transplant probability and outcomes. METHODS We included 143 consecutive heart failure patients who received a CF-VAD as a bridge-to-transplant at 3 institutions. Factors associated with post-VAD peak panel reactive antibodies (PRA) among several measurements were identified using multivariable linear regression. A parametric survival model was used to assess transplant waiting time and probability, risk of rejection, and a composite outcome of rejection, graft failure, and death. RESULTS Thirty-six patients (25%) were female; mean age was 47 ± 13 years. Eighty-one patients (57%) had a pre-VAD PRA of 0%, and 16 were highly sensitized (PRA > 80%). Age, female sex, and pre-VAD PRA were independently associated with post-VAD PRA. A 10-year increase in age was associated with a 5% decrease in post-VAD PRA (p = 0.03). Post-VAD PRA was 19% higher in women vs men (p < 0.01). A 10%-increase in pre-VAD PRA was associated with a 4.7% higher post-VAD PRA (p < 0.01). During a mean follow-up of 12 ± 11 months, 90 patients underwent cardiac transplantation. A 20% increase in post-VAD PRA was associated with 13% lower probability of transplant (hazard ratio, 0.87; 95% confidence interval, 0.76-0.99). A high PRA was not associated with adverse post-transplant outcomes. CONCLUSIONS Younger age, female sex, and pre-VAD PRA were independent predictors of elevated PRA post-VAD. Higher PRA was significantly associated with lower transplant probability but not increased rejection, graft failure, or death after transplant.

Granulocyte colony stimulating factor in chronic angina to stimulate neovascularisation: a placebo controlled crossover trial

Background Experimental studies demonstrate that granulocyte colony stimulating factor (G-CSF) promotes neovascularisation and confers cardioprotection. Objective To assess the efficacy of repeated low dose G-CSF plus exercise on myocardial ischaemia in patients with severe chronic ischaemic heart disease. Methods 18 patients with Canadian Cardiovascular Society class III–IV angina completed a randomised, double blind, crossover study of dose adjusted G-CSF versus placebo. Exercise was commenced 6 weeks prior and continued for the duration of the study. G-CSF or placebo was administered daily for 5 consecutive days at fortnightly intervals for three cycles, followed by crossover after 6 weeks. Primary outcome was myocardial perfusion by cardiac magnetic resonance imaging (MRI). Secondary outcomes were: Seattle Angina and Utility Based Quality of Life Heart Questionnaire (SAQ/UBQ-H), Exercise Stress Test (EST) and quantification of endothelial progenitor cells (EPC) by flow cytometry and angiogenic cytokines by immunoassay. Results Compared with placebo, G-CSF had no effect on myocardial ischaemia by cardiac MRI, EST or SAQ/UBQ-H, despite effective EPC mobilisation (peak fold increase: CD34+=19, CD34+CD133+=37, CD34+ vascular endothelial growth factor receptor 2 (VEGFR-2)+=5, CD34+CD133+VEGFR-2+=3; all p<0.05 vs placebo). Plasma levels of stromal cell derived factor 1, angiopoietin 1, interleukin 8 and tumour necrosis factor α decreased after a symptom limited EST while vascular endothelial growth factor and platelet derived growth factor remained unchanged. All cytokines were unchanged following G-CSF. Seven troponin I positive events occurred with G-CSF compared with three with placebo (p=0.289). High sensitivity C reactive protein and N terminal prohormone brain natriuretic peptide increased with G-CSF (both p<0.01 vs placebo). Conclusion In patients with chronic ischaemic heart disease, G-CSF mobilises EPCs but does not improve myocardial perfusion or angina. G-CSF increases plasma levels of adverse prognostic cardiac biomarkers. Clinical trial registration information Australian New Zealand Clinical Trials Registry: http://www.anzctr.org.au. Unique identifier: ACTRN012607000354482.

Highly sensitized patients in cardiac transplantation: Early outcomes from the Canadian Prioritized Organ Sharing Program

To the Editor: Cardiac transplantation in a human leukocyte antigen (HLA)-sensitized patient poses significant challenges. HLA sensitization increases waiting time to transplantation as well as the risk of post-transplant rejection, graft loss and cardiac allograft vasculopathy. Registry data show a 10% panel-reactive antibody (PRA) in 12% of patients wait-listed for heart transplant and in 9% of heart transplant recipients. Desensitization strategies have shown only varied success with no large multicenter and/or randomized, controlled trials to support this approach. In Canada, hearts are allocated nationwide and prioritized according to listing status. Criteria for listing status are shown in Table 1. In 2010, the Canadian Cardiac Transplant Network (CCTN) incorporated a Category 4 sensitized (4S) listing status based on a calculated PRA (cPRA) 80% or a cPRA 20% with 3 prior virtual positive crossmatches (VXM). Status 4 patients, followed by Status 4S patients, are placed with the highest priority. As a national sharing program, this allocation system facilitates organ procurement by enabling geographic expansion and HLA diversification of the donor organ pool. Experience from the renal transplant arena has shown that national organ sharing improves accessibility of organs to sensitized patients, patient– graft outcomes and cost-effectiveness. Similarly, implementation of a VXM protocol, compared with the prior prospective serologic crossmatch system, is expected to improve access to transplantation for sensitized patients without compromising survival outcomes. VXM removes time constraints associated with performing a prospective crossmatch at the time of transplant that may otherwise limit organ procurement for sensitized patients to local donors. In addition, mechanical circulatory support with a left ventricular assist device (LVAD) has demonstrated survival benefit. Application of LVAD therapy in the highly sensitized patient as a bridge to transplant is a further opportunity to

Clinical Outcomes of Patients Treated With Pulmonary Vasodilators Early and in High Dose After Left Ventricular Assist Device Implantation.

Right ventricular failure (RVF) is common after left ventricular assist device (LVAD) implantation and a major determinant of adverse outcomes. Optimal perioperative right ventricular (RV) management is not well defined. We evaluated the use of pulmonary vasodilator therapy during LVAD implantation. We performed a retrospective analysis of continuous-flow LVAD implants and pulmonary vasodilator use at our institution between September 2004 and June 2013. Preoperative RVF risk was assessed using recognized variables. Sixty-five patients (80% men, 50 ± 14 years) were included: 52% HeartWare ventricular assist device (HVAD), 11% HeartMate II (HMII), 17% VentrAssist, 20% Jarvik. Predicted RVF risk was comparable with contemporary LVAD populations: 8% ventilated, 14% mechanical support, 86% inotropes, 25% BUN >39 mg/dL, 23% bilirubin ≥2 mg/dL, 31% RV : LV (left ventricular) diameter ≥0.75, 27% RA : PCWP (right atrium : pulmonary capillary wedge pressure) >0.63, 36% RV stroke work index <6 gm-m/m(2)/beat. The majority (91%) received pulmonary vasodilators early and in high dose: 72% nitric oxide, 77% sildenafil (max 200 ± 79 mg/day), 66% iloprost (max 126 ± 37 μg/day). Median hospital stay was 26 (21) days. No patient required RV mechanical support. Of six (9%) patients meeting RVF criteria based on prolonged need for inotropes, four were transplanted, one is alive with an LVAD at 3 years, and one died on day 35 of intracranial hemorrhage. Two-year survival was 77% (92% for HMII/HVAD): transplanted 54%, alive with LVAD 21%, recovery/explanted 2%. A low incidence of RVF and excellent outcomes were observed for patients treated early during LVAD implantation with combination, high-dose pulmonary vasodilators. The results warrant further investigation in a randomized controlled study.

Abnormal glucose regulation in an Australian acute coronary syndrome population: A prospective study

BACKGROUND Abnormal glucose regulation (AGR) is common and an adverse risk factor in patients presenting with acute coronary syndromes (ACS). METHODS We prospectively evaluated the prevalence of AGR in 300 ACS patients. Fasting blood glucose (BGL), glycated haemoglobin (HbA1c) and urinary albumin creatinine ratio (ACR) were performed. Patients without diabetes completed an oral glucose tolerance test (OGTT) >or=4 weeks post-discharge. RESULTS On admission, AGR prevalence was 60%; 32% (n=94) with diabetes and 28% (n=83) with IFG. OGTT completed in 157 patients, detected new diabetes in 5% (n=8), IGT in 24% (n=37), and IFG in 6% (n=10). In 91 patients with normal admission fasting BGL, 25% (n=23) had AGR on OGTT. Conversely, in 62 patients with admission IFG, 50% (n=31) had a normal OGTT. Patients with versus those without AGR on OGTT had higher adjusted geometric mean HbA1c (5.92; 95% CI 5.81-6.02 vs. 5.66; 95% CI, 5.59-5.74, P=0.001) and urinary ACR (1.38; 95% CI, 0.99-1.91 vs. 0.74; 95% CI, 0.58-0.94, P=0.003) levels. CONCLUSIONS AGR is present in the majority of ACS patients and unrecognised in up to half of cases. OGTT improves the detection of AGR.

GRANULOCYTE-COLONY STIMULATING FACTOR IN ANGINA PATIENTS WITH ISCHAEMIC HEART DIESASE TO STIMULATE NEOVASCULARISATION (GAIN II TRIAL)

Background Experimental studies have demonstrated that granulocyte-colony stimulating factor (G-CSF) stimulates neovascularization and confers cardiomyocyte protection. Limited data exist for the safety and efficacy of G-CSF in patients with severe ischemic heart disease (IHD). We hypothesized that repeated low dose G-CSF administration in conjunction with exercise would mobilize bone marrow derived endothelial progenitor cells (EPC) and improve ischemia in patients with severe IHD.