Lung Transplantation in Hungary From Cardiac Surgeons' Perspective.

Thoracic organ transplantation made a fresh start in Hungary with the first double lung transplant in December 2015. This major leap in Hungarian transplantation was preceded by almost 10 years of preparation, new infrastructure development, and structural changes not only at the organizational level but in human resources as well. In the following years, until recently, altogether 47 lung transplants were performed on 24 men and 23 women. The underlying pathologies were as follows: chronic obstructive pulmonary disease, 25; cystic fibrosis, 11; idiopathic pulmonary fibrosis, 7; as well as other diseases, including bronchiectasis, eosinophilic granuloma, lymphangioleiomyomatosis, and primary pulmonary hypertension in 4 cases. The youngest recipient was 13 and the oldest was 65 years old. Overall survival rates at 30 days and at 1 year were 96% and 82%, respectively. No patients were lost in the cystic fibrosis and other diseases group, whereas the 1-year survival rates of the chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis groups were 73% and 71%, respectively. The results show the robustness and viability of the program, although there is still opportunity for further improvement. In this short paper, we summarize the fields of possible further cooperation of thoracic and cardiac teams as well as future challenges facing the new Hungarian lung transplant program.

Antibody-Mediated Rejection in a Multiple Lung Transplant Patient: A Case Report.

Lung transplant is an effective way to treat many end-stage lung diseases. However, one of the main barriers of allograft organ transplant is still the immunologic rejection of transplanted tissue, which is a response of the HLA molecules. Rejection is a complex process involving both T-cell-mediated delayed-type hypersensitivity reactions and antibody-mediated hypersensitivity reactions to histocompatibility molecules on foreign grafts. We report the case of a 25-year-old female patient with cystic fibrosis who underwent 2 lung transplants because of her initial diagnosis and appearance of bronchiolitis obliterans syndrome after the first transplant. Only 13 months after the second transplant, despite the therapies applied, a new rejection occurred associated with high mean fluorescent intensity donor-specific antibody levels, which resulted later in the death of the patient. The present case draws attention to the importance of matching HLA molecules between donor and recipient in addition to immunosuppressive therapy.

Aortic cannulation and cardiopulmonary bypass independently produce selective brain lesions in pig.

Whether cardiopulmonary bypass alone or together with the manipulation of the aorta produce neurological complication remains controversial. Using a domestic pig model of cardiopulmonary bypass, we investigated the immediate effects of aortic cannulation and cardiopulmonary bypass on neuronal injury in different brain regions. We compared the presence of neuronal injury in three experimental groups: non-operated controls (n = 3); operated controls with aortic cannulation without cardiopulmonary bypass (n = 5); operated animals undergoing cardiopulmonary bypass (n = 5). Pyknotic cells were counted in the prefrontal cortex, cerebellum and in the hippocampal formation. Calretinin immunohistochemistry was used to show possible ischemic damages in the hippocampus which is known to be one of the most sensitive brain regions to ischemia. Decreased calretinin immunoreaction and reduced number of calretinin-positive neurons were observed in the hippocampal dentate gyrus following aortic cannulation or cardiopulmonary bypass compared to the non-operated control group. Changes were more severe following cardiopulmonary bypass than after cannulation of the aorta alone. The frequency of pyknotic cell nuclei was not different in the control and experimental groups. Our experimental study suggests that both cannulation of the aorta alone and cardiopulmonary bypass affect a selected population of neurons.

The role of endothelin-B receptors in myocardial and endothelial reperfusion injury after heart transplantation.

BACKGROUND: This study was designed to investigate the effects of the selective endothelin-B (ET-B) receptor agonist IRL1620 and the selective ET-B receptor antagonist BQ788 on myocardial and endothelial function after reversible deep hypothermic ischemia and reperfusion. METHODS: Isogenic intraabdominal heterotopic heart transplantation was performed on Lewis rats. After one hour of cold ischemic preservation, reperfusion was started either after application of saline vehicle or IRL1620 or BQ788 or both. Left ventricular pressure-volume relations and myocardial blood flow were assessed after one and 24 hours of reperfusion. Endothelium-dependent vasodilatation to acetylcholine (ACH) and endothelium-independent vasodilatation to sodium nitroprusside (SNP) were also determined. RESULTS: IRL1620 attenuated and BQ788 improved myocardial contractility significantly as indicated by the left or upward shift of the systolic pressure-volume relation, respectively, and significantly changed myocardial blood flow during early reperfusion (p<0.05). Although myocardial function and baseline myocardial blood flow were similar in both groups after 24 hours of reperfusion, endothelium-dependent vasodilatation was still significantly lower in the IRL1620 and higher in the BQ788 group (p<0.05). CONCLUSIONS: These results suggest that activation of the ET-B receptors contributes to reperfusion injury after cardiac preservation in a rat heart transplant model.

Coronary metabolic adaptation restricted by endothelin in the dog heart.

Endothelin elicits long-lasting vasoconstriction in the coronary bed. This remarkable spastic response raises the question whether or not the metabolic adaptive mechanisms of the coronaries are activated under endothelin effect. The role of the compensatory mediators adenosine and inosine was investigated before and after intracoronary (i.c.) administration of endothelin-1 (ET-1, 1.0 nmol) using 1-min reactive hyperemia (RH) tests on in situ dog hearts (n=15) with or without blocking the ATP-sensitive potassium (K+(ATP)) channels by glibenclamide (GLIB, 1.0 micromol min(-1), i.c.). The release of adenosine and inosine via the coronary sinus was measured by HPLC during the first minute of RH. Endothelin-1 reduced baseline coronary blood flow (CBF) and RH response (hyperemic excess flow (EF) control vs. ET-1: 81.7+/-13.6 vs. 43.4+/-10.9 ml, P<0.01), while it increased the net nucleoside release (adenosine, control vs. ET-1: 58.9+/-20.4 vs. 113.7+/-39.4 nmol, P<0.05; inosine: 242.1+/-81.8 vs. 786.9+/-190.8 nmol, P<0.05). GLIB treatment alone did not change baseline CBF but also reduced RH significantly and increased nucleoside release (EF control vs. GLIB: 72.1+/-11.7 vs. 31.9+/-5.5 ml, P<0.01; adenosine: 18.8+/-4.6 vs. 63.0+/-24.8 nmol, P<0.05; inosine: 113.0+/-37.2 vs. 328.2+/-127.5 nmol, P<0.05). Endothelin-1 on GLIB-treated coronaries further diminished RH and increased nucleoside release (EF: 21.5+/-8.0 ml, P<0.05 vs. GLIB; adenosine: 75.3+/-28.1 nmol, NS; inosine: 801.9+/-196.6 nmol, P<0.05 vs. GLIB). The data show that ET-1 reduces metabolic adaptive capacity of the coronaries, and this phenomenon is due to decreased vascular responsiveness and not to the blockade of ischemic mediator release from the myocardium. The coronary effect of ET-1 may partially be dependent on K+(ATP) channels.

Ventricular arrhythmias induced by endothelin-1 or by acute ischemia: a comparative analysis using three-dimensional mapping.

OBJECTIVES: To analyze three-dimensional activation patterns of ventricular arrhythmias induced by endothelin-1 in comparison with ischemia-induced tachycardias. METHODS: Following AV node ablation, sixty pin electrodes containing four bipoles each were inserted into both ventricles of ten foxhounds. Using a computerized mapping system, this would allow to simultaneously record 240 endo-, epi- and midmyocardial electrograms for reconstruction of the three-dimensional activation pattern. In five dogs, endothelin-1 was infused into the LAD at 60 pmol/min. In another five animals, the LAD was ligated. During the following 40 min, all ventricular arrhythmias were recorded for subsequent analysis. Furthermore, left ventricular conduction times during constant pacing and local effective refractory periods at eight left ventricular sites were determined before and after either intervention. RESULTS: Endothelin-1 had no significant effect on conduction time and refractoriness, whereas ligation prolonged both parameters significantly. Endothelin-1 as well as ligation induced multiple mono- and polymorphic nonsustained ventricular tachycardias. Endothelin-1-induced arrhythmias were exclusively based on focal mechanisms, whereas during ligation, macroreentrant mechanisms were involved in the maintenance of tachycardias in 29% of episodes. CONCLUSION: The differences in the effects of endothelin-1 and LAD ligation on electrophysiologic properties and the difference in the mechanism of induced ventricular tachycardias support the hypothesis that, apart from vasoconstrictive properties, endothelin-1 exerts an intrinsic arrhythmogenic effect.

[Effect of regional hypothermia on cerebrospinal fluid parameters during thoracoabdominal aorta clamping in dogs]. / Regionális gerincveló hypothermia hatása a liquor összetételére thoracoabdominalis aortakirekesztés során állatkísérletben.

The most feared complication of thoracoabdominal clamping is the paraplegia or paraparesis following ischemic injury of the spinal cord. Early intraoperative recognition of this complication has not been solved yet. In our earlier experiment we found significant alterations of CSF glucose, lactate, pCO2 and Neuron Specific Enolase (NSE) levels during 60 minutes thoracoabdominal aortic clamping in dogs. The analysis of these parameters proved to be proper to follow metabolism of the spinal cord during this type of surgery. In our present paper we studied protective effect of regional hypothermia using peridural cooling by registration of above parameters. Statistical analysis of our data showed prevention of production of anaerobe metabolites in animals with icy peridural irrigation. The biochemical approach is appropriate for monitoring effectiveness of regional hypothermia of the spinal cord during aortic surgery.

Enhanced accumulation of pericardial fluid adenosine and inosine in patients with coronary artery disease.

Adenosine and inosine are believed to have cardioprotective effects. However, little is known about their possible role in the metabolic autoregulation of human coronaries and in pathologic conditions with supply/demand imbalance of the heart such as coronary artery disease. Since these low molecular weight nucleosides freely diffuse through the monolayer of the visceral pericardium, adenosine and inosine concentrations in pericardial fluid may well reflect the conditions in cardiac interstitium. The pericardial fluid and systemic venous blood adenosine and inosine concentrations were measured in 98 human subjects undergoing heart surgery for coronary artery disease or valvular heart disease. Adenosine and inosine concentrations were measured by HPLC with UV detection. In subjects with coronary artery disease pericardial fluid nucleoside concentrations were significantly higher than in patients with valvular heart disease (adenosine: 1545 (996-3146) nmol/L [median (25th-75th quartiles)] vs. 738 (390-2527) nmol/L, P<0.01; inosine: 658 (321-1331) nmol/L vs. 347 (159-1037) nmol/L, P<0.05), while in both patient groups pericardial fluid nucleoside concentrations were higher by an order of magnitude than in venous plasma. Our results show the enhanced release of adenosine and inosine by the ischemic myocardium as a marker of supply/demand imbalance and support the hypothesis that these cardiac nucleosides may have an important role in the adaptation of coronary blood flow in human coronary artery disease.

Endothelin-A and -B antagonists protect myocardial and endothelial function after ischemia/reperfusion in a rat heart transplantation model.

OBJECTIVE: Previous studies suggested that endothelin-1 (ET-1) may play a pathophysiological role in myocardial ischemia/reperfusion injury. This study was designed to investigate the effects of the selective ET-A receptor antagonist BQ123 and the selective ET-B receptor antagonist BQ788 on myocardial and endothelial function after reversible deep hypothermic ischemia in a heterotopic rat heart transplantation model. METHODS: Isogenic intraabdominal heterotopic transplantation was performed in Lewis rats. After 1 h of cold ischemic preservation reperfusion was started either after application of placebo (control), BQ123 (3 mumol/kg/min). BQ788 (3 mumol/kg/min), ET-1 (8 pmol/kg/min) or simultaneous infusion of BQ123 or BQ788 and ET-1, respectively (n = 12 each). An implanted balloon was used to obtain pressure-volume relations of the transplanted heart. Myocardial blood flow (MBF) was assessed by the hydrogen-clearance method. Measurements were taken after 1 and 24 h of reperfusion. Endothelium-dependent vasodilation to acetylcholine (ACH) and endothelium-independent vasodilation to sodium nitroprusside were also determined. RESULTS: Both BQ123 and BQ788 significantly improved myocardial and endothelial functional recovery during early reperfusion, whereas ET-1 significantly impaired myocardial and endothelial function. Simultaneous infusion of ET-1 diminished the effects of BQ123 and BQ788. Although myocardial function and baseline MBF were similar in all groups after 24 h of reperfusion, endothelium dependent vasodilation to ACH was still significantly higher in the BQ123 and BQ788 groups and lower in the ET-1 groups (p < 0.05). CONCLUSIONS: These results suggest that endogenous ET release is involved in the pathogenesis of reperfusion injury after heart transplantation. ET-A and ET-B receptor antagonists may be useful to reduce ischemia/reperfusion injury.

Endothelin-A receptor antagonist BQ123 protects against myocardial and endothelial reperfusion injury.

BACKGROUND: This study was designed to investigate the effects of the selective endothelin-A receptor antagonist BQ123 on myocardial and endothelial function after reversible deep hypothermic ischemia and reperfusion. METHODS: Isogenic intra-abdominal heterotopic heart transplantation was performed in Lewis rats. After one hour of cold ischemic preservation reperfusion was started after application of either saline vehicle or BQ123 (1 micromol/L). Left-ventricular pressure-volume relations and myocardial blood flow were assessed after one and 24 hours of reperfusion. Responses to endothelium-dependent vasodilator acetylcholine and endothelium-independent vasodilator sodium nitroprusside were also determined. RESULTS: BQ123 significantly improved myocardial contractility, as indicated by the leftward shift of the systolic pressure-volume relation and significantly increased myocardial blood flow during early reperfusion (p < 0.05). Although myocardial function and baseline myocardial blood flow were similar in both groups after 24 hours of reperfusion, endothelium-dependent vasodilatation was still significantly higher in the BQ123 group (p < 0.05). CONCLUSIONS: These results suggest that endothelin-A receptor antagonists may be useful in reducing ischemia/reperfusion injury after heart transplantation by preservation of myocardial and endothelial function.

Compensation of endothelin-1-induced coronary vasoconstriction.

The vasodilator capacity of the coronaries was determined by the reactive hyperemia (RH) test in open-chest anesthetized dogs. The myocardial release of adenine nucleosides (adenosine and inosine) was measured by the HPLC-UV method. In group I (n = 9) after the control RH test, a bolus injection of endothelin-1 (ET-1; 1.0 nmol i.c.) was administered and was followed by a second RH test. In group II (n = 9), glibenclamide (GLIB) was infused continuously (1.0 mumol/min i.c.) and RH tests were performed during the control period and then before and after bolus injection of ET-1. In contrast to the significant reduction of the RH response after ET-1 in group I and after GLIB in group II, the nucleoside release into the coronary sinus during the first minute of the RH test was significantly higher (adenosine release 0.05 +/- 0.02 vs. 0.10 +/- 0.04 mumol, and 0.02 +/- 0.00 vs. 0.08 +/- 0.02 mumol; p < 0.05). Injection of ET-1 did not result in further RH reduction in GLIB-pretreated dogs (group II) but significantly increased nucleoside release. High doses of ET-1 activated the metabolic compensatory mechanisms of the myocardium and thereby increased the release of adenine nucleosides into the venous blood of the heart. However, whether these metabolites can exert any significant compensatory vasodilator effects appears doubtful.

Increased monophasic action potential dispersion in endothelin-1-induced ventricular arrhythmias.

The aim of this study was to investigate the changes in monophasic action potentials (MAP) from different sites in the heart and to determine MAP dispersion during endothelin-1 (ET-1) infusion. Standard ECG, left ventricular anterior, right ventricular lateral, right ventricular septal, and right ventricular apical MAPs and intra-arterial blood pressure were monitored in seven anesthetized open-chest mongrel dogs. After radiofrequency atrioventricular node ablation, ventricular pacing (70/min) was performed and intracoronary ET-1 (60 pmol/min) was administered into the left anterior descending coronary artery. Both MAPd90 and MAPd90 dispersion increased significant during ET-1 infusion. The onset of spontaneous monomorphic and polymorphic sustained ventricular tachycardias (sVT) was observed in five dogs (around 40 min), and nonsustained VTs (nsVT) developed in another two dogs. The increases in MAP and MAP dispersion lasted until the appearance of polymorphic nsVTs and sVTs, but at the time of these VTs this difference decreased. At the termination of the experiments, ventricular fibrillation occurred in six cases. In four cases third-phase early afterdepolarizations were recorded. Our results suggest that increased MAP dispersion and development of EAD contribute to the arrhythmogenic action of ET-1, and these phenomena might explain the pathogenesis of a wide variety of ventricular arrhythmias with different morphology observed in this study.

[Incidence of septal aneurysm and its clinical significance]. / Az atrialis septalis aneurysma elöfordulása és klinikai jelentösége.

The authors performed 451 transesophageal echocardiographic (TEE) investigations over a period of three years and four months. Atrial septal aneurysm (ASA) was found in 40 cases. Of these, protrusion of the atrial septum towards the right atrium was observed in 17 cases, whilst oscillation of the atrial septum was noted in 23 cases. ASA was associated with patent foramen ovale (PFO) in ten patients, with type II. ASD in nine patients, with other congenital heart disease in six patients, and with other organic heart disease in eight patients. In three cases either an embolus or a tumor was detected in the left atrium, whilst in four cases with ASA there were no other organic cardiac disorders found. In ten patients there was a history of cerebral embolisation. Of these two had chronic atrial fibrillation, whilst the others had sinusrhythm. Of those who had cerebral embolisation, four patients had PFO, one patient had left atrial and auricular thrombi, whilst in four patients various organic heart problems (ischemic heart disease, left ventricular hypertrophy) were detected. In one patient with ASA there was no other cardiac abnormality detected. The authors conclude that ASA, which is often associated with PFO and ASD (in 25.0% and 22.5% of their cases, respectively) is detected in around eight percent of the patients who undergo TEE. ASA particularly when associated with PFO should be considered as a potential source of cerebral emboli. Indeed, cerebral embolisation occurred in 25% of their patients with ASA. It is recommended, that patients with ASA are treated with acetyl salicylic acid, whilst in patients with ASA and PFO anticoagulant therapy is the treatment of choice. In case of cerebral embolisation, or repeated cerebral ischemic attacks, operative interventions should be considered.

Simultaneous recordings of the monophasic action potential with silver chloride- and Ir-coated electrodes.

Ag/AgCl and Ir-coated electrodes allow the recording of the monophasic action potential (MAP) due to their electrical properties like non-polarisability. This study investigates the correlation of MAP recorded with both types of electrodes. In 20 mongrel dogs (18 +/- 6 kg) an Ag/AgCl and an Ir-coated catheter (Ir) were placed endocardially in the apex of the right ventricle. The effects of isoproterenol and verapamil were investigated during spontaneous rhythm and stimulation simultaneously recorded with both types of electrodes in 10 dogs without AV-node ablation. The correlation at different heart rates were investigated in 10 other dogs with complete AV-block. The morphology and amplitudes of MAP were comparable (AgCl: 15 +/- 7 mV; Ir: 13 +/- 8 mV). Following an i.v. bolus of 2 micrograms/kg isoproterenol the spontaneous rate increased (175 +/- 18 to 245 +/- 25 bpm). During stimulation with 250 ms cycle length the duration shortened (MAPd90: AgCl: 160 +/- 11 to 130 +/- 12 ms; Ir: 154 +/- 18 to 128 +/- 15 ms). The alterations reversed after 20 min. An i.v. bolus of 0.2 mg/kg verapamil decreased the spontaneous rate (167 +/- 11 to 104 +/- 23 bpm) and lengthened the MAPd90 (AgCl: 182 +/- 14 to 220 +/- 13 ms; Ir: 174 +/- 16 to 216 +/- 21 ms) at 300 ms stimulation. The correlation between the MAPd90 of both lead types was r = 0.98 during all measurements. Under the effect of beta-agonist and Ca(2+)-antagonist medication MAP showed a strong correlation recorded with both types of electrodes. Thus, both leads allow the recording of MAP but only the Ir-electrodes with their long-term stability are implantable and allows us to control the effects of drugs with implantable devices.