Angeline Leet

Extracorporeal Membrane Oxygenation in Primary Graft Failure After Heart Transplantation

BACKGROUND The aim of this review was to analyze our results with extracorporeal membrane oxygenation (ECMO) support for primary graft failure (PGF) in heart transplant recipients. METHODS A retrospective review of 239 consecutive patients who underwent heart transplantation between January 2000 and August 2009 was performed. Orthotopic, heterotopic, and heart lung transplants were included in this analysis. Over that time period, 54 patients developed PGF, of whom 39 patients required ECMO support. These 39 patients form the basis of this review. RESULTS Thirty-four patients (87%) were successfully weaned from ECMO and 29 (74.3%) survived to hospital discharge. There were no significant differences in wean rates or complications between central and peripheral ECMO. Comparison of survival in the 39 ECMO patients to the non-PGF patients (n = 185) showed a significantly worse survival in the ECMO group (p = 0.007). When those patients who died in the first 30 days were excluded, there was no difference in overall survival between groups (p = 0.73). CONCLUSIONS Extracorporeal membrane oxygenation provides excellent circulatory support for patients with PGF after heart transplantation with good wean and survival to discharge rates.

Effects of exercise training on exercise capacity and quality of life in patients with a left ventricular assist device: A preliminary randomized controlled trial

BACKGROUND A paucity of studies has examined the effect of exercise training after left ventricular assist device (LVAD) implantation. Previous research has demonstrated that insertion of the LVAD alone improves exercise capacity and quality of life (QOL). This study investigated whether supervised exercise training results in a further improvement. METHODS This prospective, randomized controlled trial with concealed allocation, assessor blinding, and intention-to-treat analysis investigated the effect of exercise training on exercise capacity and QOL in 14 patients who underwent LVAD insertion as a bridge to heart transplantation. Exercise training consisted of 8 weeks of gym-based aerobic and strengthening exercises 3 times a week, with a progressive mobilization program, compared with the control group that completed mobilization alone. Exercise capacity was measured before and after the intervention using maximal cardiopulmonary exercise testing and 6-minute walk distance (6MWD). QOL was measured using the Short Form 36-item assessment. RESULTS No adverse events were reported. There was a trend toward greater improvement in peak oxygen consumption (Vo(2)), 6MWD, and QOL in the exercise group (n = 7) compared with the control group (n = 7); however, no significant between-group difference was detected for improvements in peak Vo(2) [mean difference (exercise--control)] of 2.96 ml/kg/min (95% confidence interval, -1.04 to 6.97), 6MWD at 54 meters (-51 to 159 meters), and QOL scores over time (p > 0.05). CONCLUSION Exercise training is feasible and safe in patients with a LVAD. Trends toward greater improvement in exercise capacity and QOL after exercise training warrant further investigation in a larger trial.

Changes in Right Ventricular Function During Continuous-low Left Ventricular Assist Device Support

BACKGROUND Studies in explanted hearts from patients supported with a left ventricular assist device (LVAD) suggest that no or a less pronounced reverse remodeling process occurs in the right ventricle (RV) during LVAD support. The intermediate-term functional changes in RV function in patients with refractory heart failure (HF) supported with a continuous LVAD are not well characterized. METHODS Serial transthoracic echocardiograms and simultaneous measurements of biochemical surrogates of disease severity and organ perfusion were obtained in 20 patients (aged 57 +/- 17 years) with refractory HF before and after implantation of a continuous-flow LVAD (VentrAssist, Ventracor Ltd, Chatswood, Australia). RESULTS After a median (interquartile range) follow-up of 140 days (34-367 days), RV diameter was reduced (36 +/- 7 vs 33 +/- 4 mm; p = 0.04), as was right atrial area (27 +/- 5 vs 24 +/- 6 cm(2); p = .04). There was a trend toward a reduction in tricuspid annulus plane systolic excursion (14 +/- 6 vs 13 +/- 5 mm; p = .05). RV fractional area change (26% +/- 13% vs 27% +/- 10%; p = .53) and global RV dysfunction graded visually using a scale from 0 (absent) to 3 (severe dysfunction) did not change from pre-implant to follow-up (2 [1-2] vs 1.5 [0.5-2]; p = .18). The degree of global RV dysfunction at follow-up was closely related to the degree of RV dysfunction at the pre-implant study (r = 0.69; p = .001). Changes in global RV dysfunction were inversely related to changes in glomerular filtration rate (r = -0.49; p = .03). CONCLUSIONS During continuous-flow LVAD support, pre-existing RV dysfunction does not worsen in the intermediate term.

Diagnostic performance of multisequential cardiac magnetic resonance imaging in acute cardiac allograft rejection

We evaluated cardiac magnetic resonance imaging (CMR) as a non‐invasive test for cardiac allograft rejection.

Combined dyssynchrony and scar imaging with cardiac magnetic resonance imaging predicts clinical response and long-term prognosis following cardiac resynchronization therapy.

AIMS Cardiac resynchronization therapy (CRT) is advocated in advanced heart failure; however, patient selection remains challenging. We examined the utility of multi-sequential cardiac magnetic resonance imaging (CMR) in predicting outcome after CRT. METHODS AND RESULTS We performed multi-sequential CMR on 40 subjects with cardiomyopathy and advanced heart failure, despite optimized medical therapy. All patients had been recommended for CRT according to accepted clinical guidelines. Patients were defined by CMR as likely responders if they had significant mechanical dyssynchrony (> or =65 ms delay between septal and posterolateral wall contraction on cine imaging), and no transmural scarring of the anteroseptal or posterolateral wall on delayed contrast-enhanced imaging. Clinical composite score was recorded at baseline and 6 months post-CRT. Long-term follow-up (transplant-free survival) was 497 +/- 55 days post-CRT. A clinical response was achieved in 19/26 (73%) of the CMR-predicted responders and 2/12 (17%) of the CMR-predicted non-responders (P < 0.01, chi(2)). The sensitivity of CMR for prediction of clinical response to CRT was 90%, with a specificity of 59%. Transplant-free survival post-CRT was achieved in 88% of the CMR-predicted responders and 58% of the CMR-predicted non-responders (P < 0.05, Kaplan-Meier survival analysis). CONCLUSION Multi-sequential CMR identifies patients with severe cardiomyopathy who will respond to CRT with a favourable long-term prognosis.

Recovery From Anthracycline Cardiomyopathy After Long-term Support With a Continuous Flow Left Ventricular Assist Device

We report the clinical course of a 16-year-old girl in remission from non-Hodgkins lymphoma who presented in cardiogenic shock due to a severe anthracycline cardiomyopathy. The patient was initially stabilized using central extracorporeal membrane oxygenation support, followed by conversion to a left ventricular assist device. Unexpected evidence of cardiac recovery 9 months after implant enabled device weaning during a 3-month period, culminating in successful device explantation 1 year after implant. The patient survives 18 months after explant in New York Heart Association class I, on conventional heart failure medical management and metabolic therapy.

Late onset antibody-mediated rejection and endothelial localization of vascular endothelial growth factor are associated with development of cardiac allograft vasculopathy

Background. Improvements in cardiac transplant practice and immunosuppressive treatment have done much to curb the incidence of acute cellular rejection (ACR); however, antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV) remain prevalent. Recent studies have shown that allograft rejection is governed by both allogeneic and nonallogeneic factors such as inflammation. Initial studies have suggested that vascular endothelial growth factor (VEGF), a leukocyte mitogen produced by activated endothelial cells and leukocytes, may play a specific role in not only leukocyte trafficking, but also in the augmentation of ACR and development of CAV. Methods. We investigated the localization of VEGF protein using immunohistochemistry in a cohort of 76 heart transplant patients during periods of ACR and AMR and assessed the development of CAV. Results. We showed a significant correlation between lymphocytic localization of VEGF protein and severe ACR (P<0.001). Antibody-mediated rejection positive biopsies taken at 12 months posttransplantation showed significantly greater endothelial localization of VEGF than time-matched AMR negative biopsies (P=0.006). Diffuse endothelial expression of VEGF was also associated with a 2.5-fold increase in the risk of developing CAV (P=0.001). Conclusions. These results show that localization of VEGF protein to the vascular endothelium during AMR is significantly increased in patients who develop CAV. This study also highlights the potential pathogenic role of the endothelial cell in late onset AMR and the development of CAV.

Successful Bridge to Orthotopic Cardiac Transplantation with Implantation of a HeartWare HVAD in Management of Systemic Right Ventricular Failure in a Patient with Transposition of the Great Arteries and Previous Atrial Switch Procedure

A clinical case is described of a patient with a history of dextro-transposition of the great arteries (d-TGA) and prior atrial switch procedure who developed significant pulmonary hypertension whilst awaiting orthotopic cardiac transplantation. The increase in his pulmonary pressures necessitated de-listing for cardiac transplantation. A strategy of ventricular assist device (VAD) placement was then employed which provided improvement in his systemic cardiac output with left atrial off-loading to provide pulmonary vascular remodelling and consequently reduction in pulmonary vascular resistance (PVR). He was supported for a period of 408 days prior to successful orthotopic cardiac transplantation. A small number of cases with this abnormality undergoing VAD implantation have been described. Mechanical circulatory support has an important role in some patients with congenital heart disease.

Fondaparinux: An effective bridging strategy in heparin-induced thrombocytopenia and mechanical circulatory support

A 56-year-old Caucasian man with ischemic cardiomyopathy was admitted to the hospital for decompensated heart failure. Ensuing cardiogenic shock required peripheral extracorporeal membrane oxygenation (ECMO) resuscitation, followed by biventricular assist device (BiVAD) implantation with HeartWare devices (HeartWare International Inc, Framingham, MA) as a bridge to transplantation. A heparin infusion was used during ECMO and continued after the BiVAD insertion. The patient’s platelet count before heparin was initiated was 88 10/liter, reaching a nadir of 23 10/liter during therapy. Ultrasound imaging demonstrated bilateral lower limb and inferior vena cava thromboses. A diagnosis of heparininduced thrombocytopenia (HIT) with thrombosis (HITT) was made by antibody testing using the platelet factor 4/heparin enzyme-linked immunosorbent assay. Treatment with a lepirudin infusion was commenced. Aspirin (100 mg daily), dipyridamole (100 mg twice daily), and warfarin (international normalized ratio [INR] 2 to 3) were initiated after the platelets recovered as part of the VAD management protocol. Given the thrombotic risks associated with BiVADs and the extensive thromboses in this patient, management of sub-therapeutic INRs after discharge was prudent. Usual management involves patients self-administering a lowmolecular-weight heparin until the INR becomes therapeutic. Given the contraindication to heparin-based therapies in this patient, a trial was started of off-label fondaparinux (7.5 mg daily), given by sub-cutaneous self-injection, during admission between Post-operative Days 44 and 47. The patient was discharged home on Post-operative Day 49 without any negative clinical sequelae. Follow-up confirmed that the fondaparinux injections facilitated safe and effective outpatient management of sub-therapeutic INRs. Figure 1 highlights the post-operative time course and the administration of fondaparinux during periods of subtherapeutic INRs. Immune-mediated HIT is a highly pro-thrombotic adverse effect of heparin. The management of HIT includes anticoagulation with a rapidly acting non-heparin anti-coagulant to treat HITT and to prevent new or progressive thrombosis. The direct thrombin inhibitor, lepirudin, was an effective in-patient treatment; however, the presence of a highly thrombogenic BiVAD required a strategy for ambulatory anti-coagulation. Fondaparinux has been studied in the management of HITT, but not in VAD patients. Case reports have also documented successful switching from a direct thrombin inhibitor to fondaparinux for HIT using a similar strategy to that used in this patient. Despite the limited evidence for fondaparinux in HIT and the lack of evidence in VAD patients, this report provides support for its off-label use as a safe and effective anti-thrombotic agent in a BiVAD patient with HITT. This agent provides a therapeutic alternative for inpatient and outpatient management of anti-coagulation in patients who not able to receive heparin-based therapies.

A Bioavailability Study of Cyclosporine: Comparison of Neoral Versus Cysporin in Stable Heart Transplant Recipients

BACKGROUND Cyclosporine in the form of a microemulsion (Neoral) has been the cornerstone of the majority of immunosuppression regimes in thoracic organ transplantation. Cysporin, an alternative form of cyclosporine, is now available. Although bioavailability has been studied in healthy volunteers and stable renal transplant recipients, there are no bioequivalence data currently available for the population of thoracic organ transplant recipients. This randomized, 2-arm, crossover, open-label study compares the pharmacokinetic profiles of two formulations of cyclosporine (Neoral and Cysporin) in stable heart transplant patients. METHODS The pharmacokinetics of Neoral and Cysporin were assessed on 2 study days in 16 stable heart transplant recipients already receiving Neoral, who were at least 15 months post-transplant and had not undergone dose adjustments of Neoral for the previous 3 months. Participants were randomized to receive one study drug for at least 2 weeks with crossover to the other arm for a further 2 weeks. Drug levels were measured from blood samples obtained on the study day at the end of each phase at baseline (pre-dose) and 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours post-dose. RESULTS The two formulations of cyclosporine were not found to be bioequivalent for C(max). There was less cyclosporine absorbed with Cysporin than with Neoral (ratio 1.31, 90% confidence intervals 1.20 to 1.42) and, although statistically bioequivalent for area under the curve (AUC), a reduction was observed with the new formulation (ratio 1.17, 90% confidence intervals 1.1 to 1.23). The best fit with AUC was observed at 6 hours post-dose for Neoral and 1.5 hours for Cysporin, not the 2 hours post-dose used clinically. CONCLUSIONS This study suggests that Cysporin may not be clinically bioequivalent to Neoral in heart transplant recipients. The clinical implications of this observation require further exploration in a larger patient cohort.