In vivo tissue reaction within the outflow conduit in patients supported by HeartWare HVAD.

AIM: The frequency, extent, and nature of tissue ingrowth within the continuous-flow left ventricular assist device (cf-LVAD) outflow conduit has not been systematically assessed. We sought to characterize conduit histopathology at explantation in a cohort of patients with HeartWare ventricular assist device (HVAD) and assess the effect on pump performance. METHODS: Patients undergoing routine histopathological assessment of a HeartWare HVAD removed at transplantation or autopsy were assessed. Outflow conduits were examined macroscopically, and visible tissue was sectioned for microscopic evaluation. In patients who had undergone prior contrast-enhanced computerized tomography (CT) with HVAD in situ, the outflow conduit was measured at the aortic anastomosis and 5 cm proximal to the anastomosis, in the axial and sagittal planes. All patients had their pump flow, flow pulsatility, current, and speed determined from log files examined at 1, 3, 6, 9, and 12 months after LVAD implantation. RESULTS: Twenty-five consecutive patients were assessed (24 LVAD, 1 biventricular assist device (BiVAD)). Of the 26 outflow grafts assessed, there was evidence of tissue ingrowth reaction in 24 (92%) grafts. The most common site was the distal anastomosis (18/24, 75%), with the graft body involved in 14 of 24 (58%) grafts. Microscopic evaluation revealed acute inflammatory infiltrate in 4 of 24 grafts (17%), chronic inflammatory infiltrate in 14 of 24 (58%), neointima formation in 18 of 24 (75%) and fibrosis in 18 of 24 (75%) grafts. The median depth of tissue was 1 mm (range, 0-2 mm). The mean conduit diameter was 9.5 ± 0.6 mm at the aortic anastomosis compared with 11.1 ± 0.5 mm 5 cm proximal to the anastomosis (p < 0.0001). In patients with unchanged pump speed one month after implantation, analysis of log files revealed a significant (5.8 ± 8.6%) decrease in pump flow (4.65 ± 0.86 vs 4.38 ± 0.92 L/min, p = 0.01) and flow pulsatility (5.00 ± 1.10 vs 4.16 ± 1.05 L/min, p = 0.006). CONCLUSIONS: There is evidence of tissue formation within the HVAD outflow conduit in the vast majority of patients, most commonly located at the aortic anastomosis. This is associated with significantly decreased pump flow over time.

Liver and lung transplantation in cystic fibrosis: an adult cystic fibrosis centre's experience.

Liver disease develops in one-third of patients with cystic fibrosis (CF). It is rare for liver disease to have its onset after 20 years of age. Lung disease, however, is usually more severe in adulthood. A retrospective analysis was performed on nine patients. Three patients required lung transplantation approximately a decade after liver transplant, and another underwent combined liver and lung transplants. Four additional patients with liver transplants are awaiting assessment for lung transplants. One patient is awaiting combined liver and lung transplants. With increased survival in CF, several patients may require more than single organ transplantation.

Outpatient management of intra-corporeal left ventricular assist device system in children: a multi-center experience.

Little is known about the outcomes of children supported on intracorporeal left ventricular assist device (HVAD), and the feasibility of outpatient management. All centers with pediatric patients discharged from the hospital on the device were identified using company database. A total of 14 centers were contacted, with 9 centers, contributing data retrospectively. From 2011 to 2013, 12 pediatric patients (7 females), mean aged 11.9 ± 2.3 years (range 8-15), mean weight 43 ± 19 kg (range 18-81), mean body surface area 1.3 ± 0.3 m(2) (range 0.76-1.96) were identified. Diagnosis included: dilated cardiomyopathy (CMP) (n = 5), noncompaction CMP (n = 4), toxic CMP (n = 2) and viral CMP (n = 1). Indications for support were permanent support (n = 1), bridge to recovery (n = 1) and bridge to transplantation (n = 10). Prior to HVAD implantation, all patients received intravenous inotropes and two patients were on temporary mechanical support. Overall mortality was 0%. Mean duration of inpatient and outpatient support were 56 (range: 19-95 days) and 290 days (range: 42-790), respectively. Mean readmission rate was 0.02 per patient month (2.1 per patient). No adverse events involving emergency department occurred. Eight children resumed local schooling. Home discharge of children supported on HVAD is feasible and safe. School integration can be achieved. There is wide center variability to discharge practice for children.

Normothermic ex vivo perfusion provides superior organ preservation and enables viability assessment of hearts from DCD donors.

The shortage of donors in cardiac transplantation may be alleviated by the use of allografts from donation after circulatory death (DCD) donors. We have previously shown that hearts exposed to 30 min warm ischemic time and then flushed with Celsior supplemented with agents that activate ischemic postconditioning pathways, show complete recovery on a blood-perfused ex vivo working heart apparatus. In this study, these findings were assessed in a porcine orthotopic heart transplant model. DCD hearts were preserved with either normothermic ex vivo perfusion (NEVP) using a clinically approved device, or with standard cold storage (CS) for 4 h. Orthotopic transplantation into recipient animals was subsequently undertaken. Five of six hearts preserved with NEVP demonstrated favorable lactate profiles during NEVP and all five could be weaned off cardiopulmonary bypass posttransplant, compared with 0 of 3 hearts preserved with CS (p < 0.05, Fisher's exact test). In conclusion, DCD hearts flushed with supplemented Celsior solution and preserved with NEVP display viability before and after transplantation. Viability studies of human DCD hearts using NEVP are warranted.

Increasing the tolerance of DCD hearts to warm ischemia by pharmacological postconditioning.

Donation after circulatory death (DCD) offers a potential additional source of cardiac allografts. We used a porcine asphyxia model to evaluate viability of DCD hearts subjected to warm ischemic times (WIT) of 20­40 min prior to flushing with Celsior (C) solution. We then assessed potential benefits of supplementing C with erythropoietin, glyceryl trinitrate and zoniporide (Cs), a combination that we have shown previously to activate ischemic postconditioning pathways. Hearts flushed with C/Cs were assessed for functional, biochemical and metabolic recovery on an ex vivo working heart apparatus. Hearts exposed to 20-min WIT showed full recovery of functional and metabolic profiles compared with control hearts (no WIT). Hearts subjected to 30- or 40-min WIT prior to C solution showed partial and no recovery, respectively. Hearts exposed to 30-min WIT and Cs solution displayed complete recovery, while hearts exposed to 40-min WIT and Cs solution demonstrated partial recovery. We conclude that DCD hearts flushed with C solution demonstrate complete recovery up to 20-min WIT after which there is rapid loss of viability. Cs extends the limit of WIT tolerability to 30 min. DCD hearts with ≤30-min WIT may be suitable for transplantation and warrant assessment in a transplant model.

Initial experience with the balloon expandable Edwards-SAPIEN Transcatheter Heart Valve in Australia and New Zealand: the SOURCE ANZ registry: outcomes at 30 days and one year.

BACKGROUND: We report the findings of the SOURCE-ANZ registry of the clinical outcomes of the Edwards SAPIEN™ Transcatheter Heart Valve (THV) in the Australian and New Zealand (ANZ) clinical environment. METHODS: This single arm registry of select patients treated in eight centres, represent the initial experience within ANZ with the balloon expandable Edwards SAPIEN THV delivered by transfemoral (TF) and transapical (TA) access. RESULTS: The total enrolment for the study was 132 patients, 63 patients treated by TF, 56 by TA, and 2 patients were withdrawn from the study. The mean ages: 83.7 (TF) and 81.7 (TA), female: 34.3% (TF) and 61.3% (TA), logistic EuroSCORE: 26.8% (TF) and 28.8% (TA), and with procedural success (successful implant without conversion to surgery or death): 92.4% (TF) and 87.1% (TA) (p=0.32). Outcomes were not significantly different between TF and TA implants. These included one year mortality of 13.6% (TF) and 21.7% (TA) (p=0.24), MACCE: 16.7% (TF) and 28.3% (TA) (p=0.12), pacemaker: 4.6% (TF) and 8.3% (TA) (p=0.39), and VARC major vascular complication of 4.6% (TF) and 5.0% (TA) (p=0.91). CONCLUSION: TAVI in the ANZ clinical environment has demonstrated excellent outcomes for both the TA and TF approaches in highly selected patients. These results are consistent with those demonstrated in European, Canadian registries and the pivotal US clinical trials. ACTRN12611001026910.

Enhanced preservation of pig cardiac allografts by combining erythropoietin with glyceryl trinitrate and zoniporide.

Erythropoietin has a tissue-protective effect independent of its erythropoietic effect that may be enhanced by combining it with the nitric oxide donor glyceryl trinitrate (GTN) and the sodium-hydrogen exchange inhibitor zoniporide in rat hearts stored with an extracellular-based preservation solution (EBPS). We thus sought to test this combination of agents in a porcine model of orthotopic heart transplantation incorporating donor brain death and total ischaemic time of approximately 260 min. Pig hearts were stored in one of four storage solutions: unmodified EBPS (CON), EBPS supplemented with GTN and zoniporide (GZ), EBPS supplemented with erythropoietin and zoniporide (EZ), or EBPS supplemented with all three agents (EGZ). A total of 4/5 EGZ hearts were successfully weaned from cardiopulmonary bypass compared with only 2/5 GZ hearts, 0/5 CON hearts and 0/5 EG hearts (p = 0.017). Following weaning from bypass EGZ hearts demonstrated superior contractility and haemodynamics than GZ hearts. All weaned hearts displayed impaired diastolic function. Release of troponin I from EGZ hearts was lower than all other groups. In conclusion, supplementation of EBPS with erythropoietin, glyceryl trinitrate and zoniporide provided superior donor heart preservation than all other strategies tested.

Combining cariporide with glyceryl trinitrate optimizes cardiac preservation during porcine heart transplantation.

Sodium-hydrogen exchange inhibitors, such as cariporide, are potent cardioprotective agents, however, safety concerns have been raised about intravenously (i.v.) administered cariporide in humans. The aim of this study was to develop a preservation strategy that maintained cariporide's cardioprotective efficacy during heart transplantation while minimizing recipient exposure. We utilized a porcine model of orthotopic heart transplantation that incorporated donor brain death and 14 h static heart storage. Five groups were studied: control (CON), hearts stored in Celsior; CAR1, hearts stored in Celsior with donors and recipients receiving cariporide (2 mg/kg i.v.) prior to explantation and reperfusion, respectively; CAR2, hearts stored in Celsior supplemented with cariporide (10 mumol/L); GTN, hearts stored in Celsior supplemented with glyceryl trinitrate (GTN) (100 mg/L); and COMB, hearts stored in Celsior supplemented with cariporide (10 mumol/L) plus GTN (100 mg/L). A total of 5/5 CAR1 and 5/6 COMB recipients were weaned from cardiopulmonary bypass compared with 1/5 CON, 1/5 CAR2 and 0/5 GTN animals (p = 0.001). Hearts from the CAR1 and COMB groups demonstrated similar cardiac function and troponin release after transplantation. Supplementation of Celsior with cariporide plus GTN provided superior donor heart preservation to supplementation with either agent alone and equivalent preservation to that observed with systemic administration of cariporide to the donor and recipient.

ATP-sensitive potassium channel activation mimics the protective effect of ischaemic preconditioning in the rat isolated working heart after prolonged hypothermic storage.

1. Ischaemic preconditioning (IP) can significantly reduce the extent of infarct size, contractile dysfunction and necrosis in hearts from a number of animal species. Activation of ATP-sensitive potassium channels has been implicated in this process. The aims of the present study were to determine the extent to which IP preserves haemodynamic function in the rat isolated working heart model after prolonged hypothermic storage and to examine the involvement of activation of potassium channels in this process. 2. Hearts from Wistar rats were perfused on a Langendorff apparatus. After stabilization in working mode, baseline measurements of heart rate, aortic flow, coronary flow and cardiac output were performed. Hearts were randomized to one of six treatment groups: (i) untreated control; (ii) IP; (iii) 3 min perfusion with 200 mumol/L pinacidil; (iv) pinacidil vehicle; (v) 3 min perfusion with 10 mumol/L glibenclamide before IP; and (vi) 3 min perfusion with glibenclamide then pinacidil. Hearts were stored in an extracellular-based preservation solution for 6 or 12 h at 2-3 degrees C, remounted on the perfusion apparatus, stabilized as before and then haemodynamic measurements were repeated, after which time heart water contents were determined. 3. Recovery of haemodynamic function was markedly enhanced in the IP and pinacidil-treated groups compared with untreated and vehicle controls. These beneficial effects were completely blocked by glibenclamide. These results suggest that strategies for activating potassium channels in donor hearts may protect organs during hypothermic storage prior to transplantation.

The nitric oxide donor, diethylamine NONOate, enhances preservation of the donor rat heart.

BACKGROUND: Ischemia/reperfusion injury to transplanted organs may be associated with loss of endothelial release of nitric oxide. The aim of this study was to determine whether supplementation of an extracellular-based cardioplegic solution in routine clinical use at our institution with nitric oxide (as diethylamine NONOate) enhanced poststorage functionality of an isolated working heart model. METHODS: Excised hearts were ligated to an aortic cannula and immediately perfused retrogradely with oxygenated Krebs solution at a hydrostatic pressure of 100 cm H2O at 37 degrees C. This preparation was then converted to a working system by switching the supply of perfusate from the aorta to a left atrial cannula at a filling pressure of 15 cm H2O. After a 1-minute stabilization period, baseline measurements of heart rate, aortic flow, coronary artery flow, and cardiac output were performed. Oxygenated cardioplegic solution (0.1 micromol/L), with or without NONOate, was then infused into the coronary circulation. Hearts were then stored in the same solutions for 6 or 12 hours at 2 degrees to 3 degrees C. The hearts were then remounted on the perfusion apparatus and reperfused as before, and hemodynamic measurements were repeated. Water content of the hearts were then determined. RESULTS: Addition of the nitric oxide donor significantly improved all hemodynamic parameters measured after 12 hours storage and aortic flow at 6 hours storage compared with the untreated control groups. There was no significant difference between the water contents of the NONOate-treated and control groups. CONCLUSIONS: The presence of the nitric oxide donor diethylamine NONOate was associated with significantly better preservation of coronary artery flow and cardiac function in the isolated rat heart after a 12-hour period of hypothermic storage and suggests a novel use for this family of compounds in the transplantation context.

Adjunctive use of inhaled nitric oxide during implantation of a left ventricular assist device.

BACKGROUND: The aim of this study was to evaluate the efficacy of inhaled nitric oxide in the prevention and reversal of pulmonary hypertension during and after left ventricular assist device implantation. METHODS: Inhaled nitric oxide (20 ppm) was administered to seven consecutive patients undergoing implantation of a left ventricular assist device at the time of implantation and for the first 24 hours after operation. RESULTS: Withdrawal of inhaled nitric oxide at 24 hours after operation was associated with a significant rise in both the transpulmonary gradient (from 8+/-1 to 14+/-2 mm Hg, p < 0.01) and in pulmonary vascular resistance (from 110+/-19 to 196+/-32 dynes x sec x cm[-5], p < 0.01). In two patients, the rise in pulmonary vascular resistance resulted in a critical fall in left ventricular assist device flow and hemodynamic deterioration, necessitating urgent reinstitution of inhaled nitric oxide. CONCLUSION: The administration of inhaled nitric oxide at the time of left ventricular assist device implantation prevents rises in pulmonary vascular resistance that in some patients result in critical reductions in left ventricular assist device flow. We suggest that inhaled nitric oxide is a useful adjunctive treatment that should be routinely available at the time of left ventricular assist device implantation.