Gábor Széplaki

Management of hereditary angioedema in pediatric patients

Hereditary angioneurotic edema is a rare disorder caused by the congenital deficiency of C1 inhibitor. Recurring angioedematous paroxysms that most commonly involve the subcutis (eg, extremities, face, trunk, and genitals) or the submucosa (eg, intestines and larynx) are the hallmarks of hereditary angioneurotic edema. Edema formation is related to reduction or dysfunction of C1 inhibitor, and conventional therapy with antihistamines and corticosteroids is ineffective. Manifestations occur during the initial 2 decades of life, but even today there is a long delay between the onset of initial symptoms and the diagnosis of hereditary angioneurotic edema. Although a variety of reviews have been published during the last 3 decades on the general management of hereditary angioneurotic edema, little has been published regarding management of pediatric hereditary angioneurotic edema. Thus, we review our experience and published data to provide an approach to hereditary angioneurotic edema in childhood.

Strong complement activation after acute ischemic stroke is associated with unfavorable outcomes

OBJECTIVE According to data from animal models, complement activation plays a major role in the brain injury after acute ischemic stroke. Scarce findings are, however, available on the detection of complement activation products in stroke patients. METHODS We have measured plasma levels of the five complement activation products (C1rC1sC1inh, C4d, C3a, C5a and SC5b-9) in samples of 26 patients with ischemic stroke upon admission. Twenty-six patients with severe carotid atherosclerosis served as patient controls. RESULTS Levels of two activation products (SC5b-9 and C4d)) were significantly elevated in the plasma of stroke patients, SC5b-9 levels, exhibited significant positive correlation with the clinical severity of stroke, the severity of neurological deficit, as well as with the level of functional disability. CONCLUSION These findings suggest that complement activation plays an active role in the development of brain infarct. The measurement of complement activation products might help to determine the clinical prognosis after acute ischemic stroke. Furthermore, there is potential usefulness of complement modulating therapy in ischemic stroke.

The effect of long-term danazol prophylaxis on liver function in hereditary angioedema?a longitudinal study

BackgroundDanazol is a drug most widely used for the prophylaxis of hereditary angioedema resulting from the deficiency of the C1-inhibitor. Potential hepatotoxic or liver tumor-inducing side effects of long-term danazol prophylaxis have been investigated during the follow-up of hereditary angioedema patients.MethodsCharacteristic parameters of liver function (including bilirubin, GOT, GPT, γGT, total protein, ALP, LDH), as well as findings of viral serology screens and abdominal ultrasonography—determined during years 0 and 5 of follow-up of patient groups taking/not taking danazol—have been reviewed and analyzed comparatively.ResultsFrom a population of 126 hereditary angioedema patients, 46 subjects taking danazol and another 46 not taking danazol fulfilled the inclusion criteria. Longitudinal follow-up did not reveal any clinically relevant difference between the liver function parameters determined in years 0 and 5 in the two groups. Abdominal ultrasound did not detect neoplastic or other potentially treatment-related alterations of the liver parenchyma. There were no discontinuations of treatment during the study.ConclusionsOur results clearly suggest that, administered at the lowest effective dose, danazol does not induce liver injury in hereditary angioedema patients.

Low ficolin-3 levels in early follow-up serum samples are associated with the severity and unfavorable outcome of acute ischemic stroke

BackgroundA number of data indicate that the lectin pathway of complement activation contributes to the pathophysiology of ischemic stroke. The lectin pathway may be triggered by the binding of mannose-binding lectin (MBL), ficolin-2 or ficolin-3 to different ligands. Although several papers demonstrated the significance of MBL in ischemic stroke, the role of ficolins has not been examined.MethodsSera were obtained within 12 hours after the onset of ischemic stroke (admission samples) and 3-4 days later (follow-up samples) from 65 patients. The control group comprised 100 healthy individuals and 135 patients with significant carotid stenosis (patient controls). The concentrations of ficolin-2 and ficolin-3, initiator molecules of the lectin complement pathway, were measured by ELISA methods. Concentration of C-reactive protein (CRP) was also determined by a particle-enhanced immunturbidimetric assay.ResultsConcentrations of both ficolin-2 and ficolin-3 were significantly (p < 0.001) decreased in both the admission and in the follow-up samples of patients with definite ischemic stroke as compared to healthy subjects. Concentrations of ficolin-2 and ficolin-3 were even higher in patient controls than in healthy subjects, indicating that the decreased levels in sera during the acute phase of stroke are related to the acute ischemic event. Ficolin-3 levels in the follow-up samples inversely correlated with the severity of stroke indicated by NIH scale on admission. In follow-up samples an inverse correlation was observed between ficolin-3 levels and concentration of S100β, an indicator of the size of cerebral infarct. Patients with low ficolin-3 levels and high CRP levels in the follow up samples had a significantly worse outcome (adjusted ORs 5.6 and 3.9, respectively) as measured by the modified Rankin scale compared to patients with higher ficolin-3 and lower CRP concentrations. High CRP concentrations were similarly predictive for worse outcome, and the effects of low ficolin-3 and high CRP were independent.ConclusionsOur findings indicate that ficolin-mediated lectin pathways of complement activation contribute to the pathogenesis of ischemic stroke and may be additive to complement-independent inflammatory processes.

Baseline level of functional C1-inhibitor correlates with disease severity scores in hereditary angioedema

The diagnosis of hereditary angioedema (HAE) is based on complement tests. We studied for the first time the possible association between complement parameters measured at the time of diagnosis and disease severity in 115 patients with HAE. Serum levels of functional C1-inhibitor (C1-INH(f)), antigenic C1-inhibitor (C1-INH(a)), C4 and hemolytic activity of the classical pathway (CH50) were determined at the time of diagnosis. We found a significant correlation between severity scores and baseline C1-INH(f) levels, as determined by ELISA assay (p=0.0003). On the other hand, there was no correlation between severity scores and other complement parameters (C1-INH(a), C4, and CH50). We consider the correlation between severity scores and baseline C1-INH(f) levels an important pathophysiological observation. Our findings underlie the potential significance of monitoring functional C1-INH levels in relation to clinical disease course.

Long-term experience with coronary sinus side branch stenting to stabilize left ventricular electrode position

BACKGROUND Despite technical advancements, implantation of coronary sinus (CS) leads may be challenging, and dislocation remains a relevant clinical problem. OBJECTIVE The aim of this study was to investigate the effectiveness, safety, and long-term outcome of stent implantation to anchor the lead to the wall of the CS side branch. METHODS Stenting of a CS side branch was performed in 312 patients. The procedure was performed because of postoperative lead dislocation in 16 patients and because of an intraoperative unstable lead position or phrenic nerve stimulation in 296 cases. A bare metal coronary stent was introduced over a second guide wire in the same CS sheath. The stent was deposited 5-35 mm proximal to the most proximal electrode. Mechanical damage of the CS side branch or pericardial effusion was not observed owing to stenting. RESULTS During follow-up (median 28.4, interquartile range 15-37, maximum 70 months), a clinically important increase in the left ventricular pacing threshold was found in four cases and reoperation was necessary in only two patients (0.6%). Phrenic nerve stimulation was observed in 18 instances, and repositioning with an ablation catheter was performed in seven cases. Impedance measurements did not suggest lead insulation failure. Three stented leads were extracted without complication after 3-49 months owing to infection, while four leads were extracted easily during heart transplantation after 7-27 months. CONCLUSION Stent implantation to stabilize CS lead position seems to be an effective and safe procedure in prevention and treatment of CS lead dislocation in selected cases.

Elevated complement C3 is associated with early restenosis after eversion carotid endarterectomy

Early restenosis following carotid endarterectomy (CEA) is an inflammatory process leading to myointimal hyperplasia of smooth muscle cells. The risk for restenosis is increased in homozygous carriers of the normal (A) allele of mannose-binding lectin (MBL2) gene. Our objective was to study the associations of C3 and as control three non-complement acute-phase reactants (APRs) (C-reactive protein, haptoglobin and alpha2HSglycoprotein) with early restenosis following CEA. We also considered, whether MBL2 genotype relates to C3 levels and to the risk of restenosis. Concentrations of the APRs were determined by radial immunodiffusion or immunoturbidimetric methods in 64 patients who underwent eversion CEA and were followed up with carotid duplex scan (CDS) examinations for at least one year. MBL2 genotypes were determined by a PCR-SSP method. C3 levels increased during the follow-up and correlated with the percentage of restenosis detected by CDS at 14 months postsurgery, in MBL2 A/A allele carriers. Patients with high C3 levels had nearly five-fold higher odds for the presence of significant restenosis (>50% reduction in diameter) even after adjusting for MBL2 genotype, age and gender. By contrast, no such associations were detected between the non-complement APRs and early restenosis. C3 is associated with and might have a direct role in the development of an early restenosis following CEA, which is partially related to an intact MBL lectin pathway, thus determining C3 levels might have clinical importance. On the other hand, our results indicate that the regulation of C3 differs from non-complement APRs.

Ablation of the Epicardial Substrate in the Right Ventricular Outflow Tract in a Patient With Brugada Syndrome Refusing Implantable Cardioverter Defibrillator Therapy

Brugada syndrome is associated with a high risk of sudden cardiac death. Currently, the cornerstone of therapy is implantation of an implantable cardioverter defibrillator (ICD). Recently, a novel approach to preventively ablate the substrate located in the anterior epicardial region of the right ventricular outflow tract showed promising results by reducing the number of ventricular fibrillation episodes in patients with ICD. Here we report on a patient with Brugada syndrome who refused ICD therapy in whom a successful epicardial right ventricular outflow tract substrate ablation was performed. In some special cases, ablation therapy might be considered as the sole therapeutic option for these patients.

Usefulness of electroanatomical mapping during transseptal endocardial left ventricular lead implantation

AIM Failure rate to implant left ventricular (LV) lead transvenously is 4-8% in cardiac resynchronization therapy (CRT) patients. Epicardial lead placement is an alternative method and if not applicable case reports and small series showed the feasibility of endocardial LV lead implantation. Electroanatomical mapping might be a useful tool to guide this procedure. METHODS AND RESULTS Four patients had undergone endocardial LV lead implantation after unsuccessful transvenous implantation or epicardial LV lead dysfunction using the transseptal approach. Electroanatomical mapping was used to mark the location of the transseptal puncture. This location point guided the mapping catheter from the subclavian access and facilitated positioning of the LV lead at the adjacent latest activation area of the left ventricle detected by activation mapping. Endocardial active fixation LV leads were successfully implanted in all patients with stable electrical parameters immediately after implantation and over a mean follow-up of 18.3 months (lead impedance 520 ± 177 vs. 439 ± 119 Ω and pacing threshold 0.8 ± 0.2 V, 0.5 ms vs. 0.6 ± 0.1 V, 0.5 ms, respectively). Patients were maintained on anticoagulation therapy with a target international normalized ratio of 3.5-4.5 and did not show any thromboembolic, haemorrhagic events, or infection. Echocardiography showed significant improvement of LV systolic function with marked improvement of the functional status. CONCLUSIONS Electroanatomical mapping is a useful technical tool to guide endocardial LV lead implantation. It helps to identify the location of the transseptal puncture and the use of activation mapping might facilitate location of the optimal lead positions during CRT.

Early complement activation follows eversion carotid endarterectomy and correlates with the time of clamping of the carotid artery

BACKGROUND Complement activation plays an important role in ischemia/reperfusion (I/R) injury. The objective of the present study was to detect the presence and mechanism of complement activation in patients who underwent carotid endarterectomy (CEA). METHODS Complement activation products C1rsC1-inhibitor, C4d, C3a and SC5b-9 and concentrations of C-reactive protein (CRP) were measured in samples serially taken from 16 patients with eversion CEA and 10 with carotid artery stenting (CAS) in the first 24h post-surgery/intervention. MBL2 genotypes were also determined. RESULTS In patients with CEA an intense increase in C3a levels were observed immediately after surgery (p<0.001), accompanied by a slight elevation in SC5b-9 levels (p<0.05). C3a levels remained elevated until 4h post-surgery, compared with the baseline values and with CAS patients. Peak C3a levels correlated with the time of carotid clamping (r=0.5921, p=0.02). No significant changes were detected in C1rsC1-inhibitor or C4d levels following CEA, and we found no association between the generation of C3a and MBL2 genotypes or CRP levels. Complement activation was not present in patients with CAS. CONCLUSIONS Early complement activation follows CEA and correlates with the time of I/R injury. The lack of C4d generation suggests the role of the alternative and not the lectin pathway in the process.