Endomyocardial substrate of ventricular arrhythmias in patients with autoimmune rheumatic diseases.

INTRODUCTION: Delayed enhancement-magnetic resonance imaging (DE-MRI) has demonstrated that nonischemic cardiomyopathy is mainly characterized by intramural or epicardial fibrosis whereas global endomyocardial fibrosis suggests cardiac involvement in autoimmune rheumatic diseases or amyloidosis. Conduction disorders and sudden cardiac death are important manifestations of autoimmune rheumatic diseases with cardiac involvement but the substrates of ventricular arrhythmias in autoimmune rheumatic diseases have not been fully elucidated. METHODS AND RESULTS: 20 patients with autoimmune rheumatic diseases presenting with ventricular tachycardia (VT) (n = 11) or frequent ventricular extrasystoles (n = 9) underwent DE-MRI and/or endocardial electroanatomical mapping of the left ventricle (LV). Ten patients with autoimmune rheumatic diseases underwent VT ablation. Global endomyocardial fibrosis without myocardial thickening and unrelated to coronary territories was detected by DE-MRI or electroanatomical voltage mapping in 9 of 20 patients with autoimmune rheumatic diseases. In the other patients with autoimmune rheumatic diseases, limited regions of predominantly epicardial (n = 4) and intramyocardial (n = 5) fibrosis or only minimal fibrosis (n = 2) were found using DE-MRI. Endocardial low-amplitude diastolic potentials and pre-systolic Purkinje or fascicular potentials, mostly within fibrotic areas, were identified as the targets of successful VT ablation in 7 of 10 patients with autoimmune rheumatic diseases. CONCLUSION: Global endomyocardial fibrosis can be a tool to diagnose severe cardiac involvement in autoimmune rheumatic diseases and may serve as the substrate of ventricular arrhythmias in a substantial part of patients.

Catheter ablation of ventricular arrhythmias and in-hospital mortality: insights from the German-wide Helios hospital network of 5052 cases.

AIMS: Catheter ablation (CA) of ventricular arrhythmias is one of the most challenging electrophysiological interventions with an increasing use over the last years. Several benefits must be weighed against the risk of potentially life-threatening complications which necessitates a steady reevaluation of safety endpoints. Therefore, the aims of this study were (i) to investigate overall in-hospital mortality in patients undergoing such procedures and (ii) to identify variables associated with in-hospital mortality in a German-wide hospital network. METHODS AND RESULTS: Between January 2010 and September 2018, administrative data provided by 85 Helios hospitals were screened for patients with main or secondary discharge diagnosis of ventricular tachycardia (VT) or premature ventricular contractions (PVCs) in combination with an arrhythmia-related CA using ICD- and OPS codes. In 5052 cases (mean age 60.9 ± 14.3 years, 30.1% female) of 30 different hospitals, in-hospital mortality was 1.27% with a higher mortality in patients ablated for VT (1.99%, n = 2, 955) compared to PVC (0.24%, n = 2, 097, P < 0.01). Mortality rates were 2.06% in patients with ischaemic heart disease (IHD, n = 2, 137), 1.47% in patients with non-ischaemic structural heart disease (NIHD, n = 1, 224), and 0.12% in patients without structural heart disease (NSHD, n = 1, 691). Considering different types of hospital admission, mortality rates were 0.35% after elective (n = 2, 825), 1.60% after emergency admission/hospital transfer <24 h (n = 1, 314) and 3.72% following delayed hospital transfer >24 h after initial admission (n = 861, P < 0.01 vs. elective admission and emergency admission/hospital transfer <24 h). In multivariable analysis, a delayed hospital transfer >24 h [odds ratio (OR) 2.28, 95% confidence interval (CI) 1.59-3.28, P < 0.01], the occurrence of procedure-related major adverse events (OR 6.81, 95% CI 2.90-16.0, P < 0.01), Charlson Comorbidity Index (CCI, OR 2.39, 95% CI 1.56-3.66, P < 0.01) and its components congestive heart failure (OR 8.04, 95% CI 1.71-37.8, P < 0.01), and diabetes mellitus (OR 1.59, 95% CI 1.13-2.22, P < 0.01) were significantly associated with in-hospital death. CONCLUSIONS: We reported in-hospital mortality rates after CA of ventricular arrhythmias in the largest multicentre, administrative dataset in Germany which can be implemented in quality management programs. Aside from comorbidities, a delayed hospital transfer to a CA performing centre is associated with an increased in-hospital mortality. This deserves further studies to determine the optimal management strategy.

Magnetic resonance imaging abnormalities in the basal interventricular septum of patients with left ventricular outflow tract arrhythmias.

INTRODUCTION: Concealed structural abnormalities were detected by delayed enhancement - magnetic resonance imaging (DE-MRI) in patients with apparently idiopathic tachycardia of left ventricular (LV) origin. Basal septal fibrosis was evaluated as a potential arrhythmia substrate in patients with left ventricular outflow tract (LVOT) arrhythmias. METHODS AND RESULTS: A total of 22 patients with LVOT arrhythmias, including frequent monomorphic premature ventricular complexes (PVCs) in 15 patients and ventricular tachycardia (VT) in 7 patients, underwent catheter ablation and DE-MRI. A total of 19 patients with frequent PVCs and 17 patients with idiopathic VT of other origin served as a control group. Basal septal intramural fibrosis as thin strip-shaped intramyocardial DE or as marked intramyocardial DE involving >25% of wall thickness was detected more frequently in patients with LVOT arrhythmias (41% and 32%) than in patients with non LVOT arrhythmias (14% and 3%). After successful ablation, 4/16 patients with basal septal intramural fibrosis and LVOT PVCs (n = 3) or LVOT VT (n = 1) compared with no patient without basal septal fibrosis experienced episodes of sustained VT with similar or different QRS morphology resulting in ICD therapy in three patients. Follow-up DE-MRI after PVC ablation (17 ± 7 months) revealed an increase in LV ejection fraction from 49 ± 5% to 56 ± 5% (n = 9) but the amount of septal DE remained unchanged. CONCLUSIONS: Basal septal intramural fibrosis may serve as the arrhythmia substrate in a substantial part of patients with premature ventricular complexes (PVCs) and VT originating from the LVOT and identifies patients with continued risk for VT recurrence after initially successful ablation of LVOT arrhythmias.

Cardiac tamponade in catheter ablation of atrial fibrillation: German-wide analysis of 21 141 procedures in the Helios atrial fibrillation ablation registry (SAFER).

Aims: Catheter ablation is an established therapy in patients with symptomatic atrial fibrillation (AF) with increasing popularity. Pericardial effusion requiring intervention (PE) is one of the most threatening adverse outcomes. The aim of this study was to examine rates of PE after catheter ablation in a large 'real-world' data set in a German-wide hospital network. Methods and results: Using ICD and OPS codes, administrative data of 85 Helios hospitals from 2010 to 2017 was used to identify AF catheter ablation cases [Helios atrial fibrillation ablation registry (SAFER)]. PE occurred in 0.9% of 21 141 catheter ablation procedures. Patients with PE were significantly older, to a higher percentage female, had more frequently hypertension, mild liver disease, diabetes with chronic complications, and renal disease. Low hospital volume (<50 procedures per year) and radiofrequency ablation (vs. cryoablation) were significantly associated with PE. Using two logistic regression models, age, female gender, hypertension, mild liver disease, diabetes with chronic complications, renal disease, low hospital volume, and radiofrequency ablation remained independent predictors for PE. Conclusion: Overall PE rate was 0.9%. Predictors for PE occurrence involved factors ascribed to the patient (age, gender, comorbidities), the type of catheter ablation (radiofrequency), and the institution (low-volume centres).

Long-term outcomes after event-free cardioverter defibrillator implantation: comparison between patients discharged within 24 h and routinely hospitalized patients in the German DEVICE registry.

AIMS: To analyse the long-term safety of implantable cardioverter defibrillators (ICDs) in patients discharged within 24 h or after 2- 5-day hospitalization, respectively, after complication-free implantation, in circumstances of actual care. METHODS AND RESULTS: Patients in the multicentre, nationwide German DEVICE registry were contacted 12-15 months after their first ICD implantation or device replacement. Data were collected on complications, potential arrhythmic events, syncope, resuscitation, ablation procedures, cardiac events, hospitalizations, heart failure status, change of medication, and quality of life. Of 2356 patients from 43 centres, 527 patients were discharged within 24 h and 1829 were hospitalized routinely for >24 h after complication-free implantations. The disease profiles and rates of co-morbidities were similar at baseline for both cohorts. During between 384 and 543 days of follow-up, there were no significant differences between the groups in terms of complications, hospitalizations, or quality of life. One-year rates of death were 4.5% in patients discharged early compared with 7.2% in hospitalized patients (hazard ratio 0.65; 95% confidence interval 0.42-1.02; P = 0.052). Rates of major adverse cardiovascular events or defibrillator events were not higher in patients discharged after 24 h. In both groups, a high rate of patients declared that they would opt for the procedure again in the same situation. CONCLUSION: Data from a large-scale registry reflecting current day-to-day practice in Germany suggest that most patients can be discharged safely within 24 h of successful ICD implantation if there are no procedure-related events. Follow-up data up to 1.5 years after implantation did not raise long-term safety concerns.

Recording of low-amplitude diastolic electrograms through the coronary veins: a guide for epicardial ventricular tachycardia ablation.

AIMS: The purpose of the study was to evaluate the role of coronary venous mapping to identify epicardial ventricular tachycardia (VT) in patients with structural heart disease. METHODS AND RESULTS: Epicardial mapping of the electrophysiological substrate through the coronary vein branches using a 2.2F, 16-pole microelectrode catheter was performed in 33 consecutive patients undergoing VT ablation. Twenty-six patients had a history of myocardial infarction and seven had a non-ischaemic cardiomyopathy. Endocardial ablation was successful in 19 of the 33 patients (58%). Low-amplitude fractionated diastolic electrograms with an electrogram-QRS interval amounting to 30-70% of the VT cycle length were recorded during the VT in the coronary vein branches in eight patients (24%). Endocardial ablation failed in seven of the eight patients with diastolic electrograms in the coronary veins, suggesting an epicardial involvement of the VT re-entry circuit. Among the patients with a suspected epicardial VT origin, four patients underwent epicardial ablation using a pericardial access after unsuccessful endocardial ablation which eliminated mappable VTs in all. CONCLUSION: Recording of low-amplitude fractionated diastolic electrograms through the coronary veins facilitates the identification of VTs with an epicardial origin requiring mapping and ablation through a pericardial access.

Protected risk stratification with the wearable cardioverter-defibrillator: results from the WEARIT-II-EUROPE registry.

BACKGROUND: The prospective WEARIT-II-EUROPE registry aimed to assess the value of the wearable cardioverter-defibrillator (WCD) prior to potential ICD implantation in patients with heart failure and reduced ejection fraction considered at risk of sudden arrhythmic death. METHODS AND RESULTS: 781 patients (77% men; mean age 59.3 ± 13.4 years) with heart failure and reduced left ventricular ejection fraction (LVEF) were consecutively enrolled. All patients received a WCD. Follow-up time for all patients was 12 months. Mean baseline LVEF was 26.9%. Mean WCD wearing time was 75 ± 47.7 days, mean daily WCD use 20.3 ± 4.6 h. WCD shocks terminated 13 VT/VF events in ten patients (1.3%). Two patients died during WCD prescription of non-arrhythmic cause. Mean LVEF increased from 26.9 to 36.3% at the end of WCD prescription (p < 0.01). After WCD use, ICDs were implanted in only 289 patients (37%). Forty patients (5.1%) died during follow-up. Five patients (1.7%) died with ICDs implanted, 33 patients (7%) had no ICD (no information on ICD in two patients). The majority of patients (75%) with the follow-up of 12 months after WCD prescription died from heart failure (15 patients) and non-cardiac death (15 patients). Only three patients (7%) died suddenly. In seven patients, the cause of death remained unknown. CONCLUSIONS: Mortality after WCD prescription was mainly driven by heart failure and non-cardiovascular death. In patients with HFrEF and a potential risk of sudden arrhythmic death, WCD protected observation of LVEF progression and appraisal of competing risks of potential non-arrhythmic death may enable improved selection for beneficial ICD implantation.

Different forms of ventricular tachycardia involving the left anterior fascicle in nonischemic cardiomyopathy: critical sites of the reentrant circuit in low-voltage areas.

INTRODUCTION: The purpose of this study was to examine the reentrant circuit of ventricular tachycardias (VTs) involving the left anterior fascicle (LAF) in nonischemic cardiomyopathy. METHODS AND RESULTS: Six patients with nonischemic cardiomyopathy presented with VTs involving the LAF. Potentials in the diastolic or presystolic phase of the VT were identified close to the LAF in 3 patients and in the mid or inferior left ventricular (LV) septum in 3 patients. Superimposed on a CARTO or NavX 3-dimensional voltage map, the diastolic and presystolic potentials were recorded within or at the border of a low-voltage zone in the LV septum in all cases. In 2 patients, both left bundle fascicles participated in the reentrant circuit including a possible interfascicular VT in one case. Ablation targeting the diastolic or presystolic potentials near the LAF or in the midinferior LV septum eliminated the VTs in all patients with the occurrence of a left posterior fascicular block and the delayed occurrence of a complete atrioventricular block in each one patient. During the follow-up of 23 +/- 20 months after ablation, 4 patients were free of ventricular tachyarrhythmias. Due to detoriation of heart failure, one patient died after 12 months and one patient underwent heart transplantation after 40 months. CONCLUSIONS: Slow conduction in diseased myocardium close to the LAF or in the middle and inferior aspects of the LV septum may represent the diastolic pathway of VT involving the LAF.

Successful use of transvenous coil electrodes as single element subcutaneous array leads.

For implantable cardioverter defibrillator a 10 J safety margin between the defibrillation threshold (DFT) and the maximum output of the device is intended. In complex cases, the additional placement of a subcutaneous array lead is a common strategy for lowering the DFT. We report the successful use of transvenous coil electrodes as single element subcutaneous array leads in order to lower the DFT.

Electrocardiographic criteria of epicardial ventricular tachycardia with anterior origin.

BACKGROUND: ECG criteria for identifying an epicardial origin of ventricular tachycardia (VT) have mainly been described for VTs with basal-superior and lateral origin. OBJECTIVE: The aim of this study was to determine ECG criteria for epicardial VTs with anterior origin as a guide for trans-pericardial ablation. RESULTS: Among 22 patients undergoing successful ablation of VTs from the anterior myocardial wall, 14 patients underwent endocardial ablation and 8 patients underwent epicardial ablation. VTs with anterior origin ablated epicardially had widened QS complexes in precordial leads with staircase-shaped notching and slowing of the descent to the nadir of S. In comparison, endocardial VTs with anterior origin usually had narrower QS complexes with a smooth and fast downstroke to the nadir of S. The duration of the negative pseudodelta wave was longer in epicardial VTs (55 ± 12 ms) compared to endocardial VTs (22 ± 12 ms). The interval "time to the nadir of S" in patients with anterior VT origin was longer in epicardial VTs (121 ± 16 ms) than in endocardial VTs (80 ± 22 ms). The QRS duration was also longer in patients with epicardial origin (212 ± 19 ms) than with endocardial VT origin (166 ± 30 ms). CONCLUSIONS: Epicardial origin of VTs arising from the anterior myocardial wall produces a slowing, widening and staircase-shaped notching in the initial VT-QS complex. Thus, the morphology of the initial part of the QS complex in precordial leads can be used as a guide for trans-pericardial ablation of VTs with anterior origin.

Analysis during sinus rhythm and ventricular pacing of reentry circuit isthmus sites in right ventricular cardiomyopathy.

BACKGROUND: The entrainment mapping algorithm is used for ablation of ventricular tachycardia (VT) in right ventricular (RV) cardiomyopathy, but ablation at endocardial isthmus sites has only a moderate success rate. This study was performed to identify additional local electrogram characteristics associated with successful ablation. PATIENTS AND METHODS: Using entrainment mapping, 45 reentry circuit isthmus sites were detected in 11 patients with RV cardiomyopathy presenting with 13 monomorphic VTs. Local bipolar electrograms were retrospectively analyzed at reentry circuit isthmus sites during VT, sinus rhythm, and programmed stimulation from the right ventricular apex (RVA), and compared between successful and unsuccessful ablation sites. RESULTS: Ablation was successful at 10 reentry circuit isthmus sites and unsuccessful at 35 isthmus sites. During VT, a longer endocardial activation time relative to QRS onset, an increased electrogram-QRS interval as a percentage of VT cycle length, and a longer electrogram duration were found at successful in comparison to unsuccessful ablation sites. The presence of isolated diastolic potentials during sinus rhythm at reentry circuit isthmus sites, consistent with slow conduction or unidirectional conduction block, was associated with successful catheter ablation. Prolongation of the duration of the local multipotential electrogram by >100 ms during programmed RVA pacing at reentry circuit exit sites, indicating functional conduction disorder was also a marker of successful ablation. CONCLUSIONS: The demonstration of multipotential electrogram characteristics indicating fixed or functional conduction block may increase the likelihood of successful VT ablation at exit and central isthmus sites of reentry circuits in RV cardiomyopathy.

Genetic modifiers that aggravate the neurological phenotype of the wobbler mouse.

The autosomal recessive mutation wobbler of the mouse (phenotype WR; genotype wr/wr) causes muscular atrophy due to motoneuron degeneration with 100% penetrance on the standard Mus musculus laboratorius C57BL/6J background. In inter- and backcrosses with M. m. castaneus strain CAST/EI we have observed a variability in the severity of neurological symptoms. Approximately 15% of the WR (wr/wr) CAST/B6 hybrids were modified wobbler (WR*) mice defined by an aggravated neuromuscular phenotype with hindlimbs severely affected in addition to forelimbs. Histologically the overt WR* phenotype was paralleled by a caudally extended neurodegeneration in the ventral horn of the spinal cord with severe astrogliosis, and levels of acetylcholine receptor alpha-subunit mRNA in leg muscle much higher than in standard WR mice. Segregation analysis, using 68 polymorphic autosomal markers in a whole genome scan, revealed a major modifier gene locus, termed wrmod1, on chromosome 14. Individual recombination events in chromosome 14 consomic mice narrowed the wrmod1 candidate region to a 29 cM interval between D14MIT154 and D14MIT105, a region homologous to human chromosome 13q. Our analysis provides access to genes that modify neurodegeneration, the human counterparts of which may be responsible for the variable expression of hereditary spinal muscular atrophies.

Comparative transcription map of the wobbler critical region on mouse chromosome 11 and the homologous region on human chromosome 2p13-14.

BACKGROUND: To support the positional cloning of the mouse mutation wobbler (wr) the corresponding regions on human Chr2p13-14 and mouse Chr11 were analyzed in detail and compared with respect to gene content, order, and orientation. RESULTS: The gene content of the investigated regions was highly conserved between the two species: 20 orthologous genes were identified on our BAC/YAC contig comprising 4.5 Mb between REL/Rel and RAB1A/Rab1a. Exceptions were pseudogenes ELP and PX19 whose mouse counterparts were not located within the analyzed region. Two independently isolated genomic clones indicate an inversion between man and mouse with the inverted segment being identical to the wobbler critical interval. We investigated the wobbler critical region by extensive STS/EST mapping and genomic sequencing. Additionally, the full-length cDNA sequences of four newly mapped genes as well as the previously mapped gene Otx1 were established and subjected to mutation analysis. Our data indicate that all genes in the wr critical region have been identified. CONCLUSION: Unexpectedly, neither mutation analysis of cDNAs nor levels of mRNAs indicated which of the candidate genes might be affected by the wr mutation. The possibility arises that there might be hitherto unknown effects of mutations, in addition to structural changes of the mRNA or regulatory abnormalities.

Impact of real-time contact force and impedance measurement in pulmonary vein isolation procedures for treatment of atrial fibrillation.

BACKGROUND: Pulmonary vein isolation (PVI) is an established procedure to treat atrial fibrillation (AF). New techniques are necessary to improve procedural parameters like shortening of procedure duration. Real-time contact force (CF) catheters are new tools aiming to improve PVI by optimizing electrode-tissue contact and generating more effective lesions. Objective of this study was to investigate the influence on procedural parameters and clinical outcome by using a CF catheter for PVI. METHODS: PVI was performed on 67 consecutive patients using a CF catheter (n = 32) or a standard ablation catheter (SAC, n = 35). Study endpoints included number of energy applications, impedance drop, fluoroscopy time, and left atrial (LA) procedure time and freedom from AF after 6 and 12 months. RESULTS: Procedural endpoint was reached in all patients with a similar clinical outcome (freedom from AF) in both groups 6 months (62.9 vs. 62.5%) and 12 months post PVI (59.4 vs. 62.9% in CF vs. SAC group, respectively). However, CF-guided ablation resulted in a greater fall of impedance (6.58 ± 0.33 vs. 9.09 ± 0.53 Ω, *** p < 0.001), lower number of energy applications (44.20 ± 3.67 vs. 34.06 ± 3.11, * p < 0.05), reduction of LA procedure time (95.52 ± 7.35 vs. 78.08 ± 7.23* min) and a significant reduction of fluoroscopy time (51.4 ± 3.3 vs. 33.0 ± 2.7*** min). In addition, a detailed analysis showed a significant correlation between quantitative impedance drop and amount of CF applied, suggesting more efficient lesion creation by CF-guided ablation. CONCLUSION: Use of CF catheters in PVI has a beneficial effect on procedural parameters, probably by improving efficacy of transmural lesion formation.

Electrocardiogram-gated 18F-FDG PET/CT hybrid imaging in patients with unsatisfactory response to cardiac resynchronization therapy: initial clinical results.

UNLABELLED: The present study aimed to distinguish responders to cardiac resynchronization therapy (CRT) from nonresponders, using electrocardiogram-gated 18F-FDG PET/CT. METHODS: Seven consecutive CRT nonresponders were included in the study, along with 7 age- and sex-matched CRT responders, serving as reference material. Therapy response was defined as clinical improvement (≥1 New York Heart Association class) and evidence of reverse remodeling. Besides PET/CT, we measured brain natriuretic peptide levels and assessed dyssynchrony using transthoracic echocardiography. RESULTS: Compared with nonresponders, CRT responders showed significant differences in the declines of left-ventricular end-systolic volume and brain natriuretic peptide and in left-ventricular dyssynchrony (global left-ventricular entropy), extent of the myocardial scar burden, and biventricular pacemaker leads positioned within viable myocardial regions. Among the nonresponders, further therapy management was guided by the PET/CT results in 4 of 7 patients. CONCLUSION: Cardiac hybrid imaging using gated 18F-FDG PET/CT enabled the identification of potential reasons for nonresponse to CRT therapy, which can guide subsequent therapy.

Usefulness of short-term variability of QT intervals as a predictor for electrical remodeling and proarrhythmia in patients with nonischemic heart failure.

The high incidence of sudden cardiac death in heart failure (HF) reflects electrophysiologic changes in response to myocardial failure. We previously showed that short-term variability of QT intervals (STV(QT)) identifies latent repolarization disorders in patients with drug-induced or congenital long QT syndrome. This study sought to determine (1) if STV(QT) is increased in patients with dilated cardiomyopathy (DC) and moderate congestive HF and (2) if increased STV(QT) is associated with ventricular arrhythmia in patients with HF. Sixty patients (53 +/- 12 years of age, 14 women) with DC and moderate HF (New York Heart Association classes II to III) were compared to matched controls. Twenty patients had implantable cardiac defibrillators secondary to a history of ventricular tachycardia (VT). Two cardiologists blinded to diagnosis manually measured QT intervals. Beat-to-beat variability of repolarization was determined from Poincaré plots of 30 consecutive QT intervals as was STV(QT). QTc intervals were comparable in patients and controls (419 +/- 36 vs 415 +/- 32 ms, respectively, p >0.05), whereas STV(QT) was significantly higher in patients with HF (7.8 +/- 3 vs 4.1 +/- 2 ms, respectively, p <0.05). STV(QT) was more increased in patients with a history of VT compared to those without VT (10.1 +/- 2 vs 6.6 +/- 2 ms, respectively, p <0.05). Increased STV(QT) and decreased ejection fraction were associated with a history of VT; however, STV(QT) was the strongest indicator. In conclusion, the present study demonstrates for the first time that STV(QT) is increased in patients with DC with HF. Patients with DC and HF and implantable cardiac defibrillators for secondary prevention had the highest STV(QT). Thus, increased STV(QT) in the context of moderate HF may reflect a latent repolarization disorder and increased susceptibility to sudden death in patients with DC, which is not identified by a prolonged QT interval.

Analysis of parathyroid graft rejection suggests alloantigen-specific production of nitric oxide by iNOS-positive intragraft macrophages.

BACKGROUND: During acute rejection of organ or tissue allografts T cells and macrophages are dominant infiltrating cells. CD4-positive T cells are important for the induction of allograft rejection and macrophages are important effector cells mediating cytotoxicity via production of nitric oxide (NO) by the inducible NO-synthase (iNOS). In the present study we analysed whether the destruction of primarily nonvascularised parathyroid allografts is also mediated by iNOS-positive macrophages. METHODS: Hypocalcaemic Lewis rats received parathyroid isografts (from Lewis donors) and allografts (from Wistar Furth donors), respectively, under the kidney capsule. Levels of serum calcium above 2 mmol/L correlated with normal parathyroid function and below 2 mmol/L with parathyroid rejection. Accelerated parathyroid allograft rejection was induced by immunisation of Lewis recipients with the allogeneic peptide P1. RESULTS: Determination of serum calcium levels is a useful parameter to control parathyroid graft function, and therefore to determine allograft rejection. Macrophages positive for both major histocompatibility complex (MHC) class II molecules and costimulatory molecules accumulated in iso- and allografts, but iNOS-positive macrophages were only detectable in allografts in the presence of activated CD4-positive T cells. These results confirm a cooperation between activated T cells and intragraft macrophages to induce macrophage iNOS expression. Recipients immunised with the allogeneic peptide P1 demonstrated accelerated rejection of allografts (mean+/-SD: 9.2+/-0.9 days) in contrast to nonimmunised animals (mean+/-SD: 15.8+/-1.8 days). Allografts of P1-immunised animals were infiltrated faster by activated CD4-positve T cells and, in addition, the infiltrates of iNOS-positive macrophages were stronger than those in allografts of nonimmunised animals. CONCLUSIONS: Intragraft iNOS-positive macrophages seem to be able to produce cytotoxic NO involved in the killing of allogeneic cells during the alloimmune response against primarily nonvascularised parathyroid organ grafts. Infiltrates of iNOS-negative macrophages found in parathyroid isografts were caused by antigen-independent inflammation triggered by surgically induced injury. The absence of activated T cells in isografts and their presence in allografts underlines their importance in inducing macrophage iNOS expression.

Reinitiation of ventricular macroreentry within the His-Purkinje system by back-up ventricular pacing - a mechanism of ventricular tachycardia storm.

BACKGROUND: We describe immediate reinitiation of macroreentry ventricular tachycardia (VT) involving the His-Purkinje system by ventricular pacing from the electrode of an implantable cardioverter defibrillator (ICD) as a mechanism of VT storm refractory to ICD therapy. METHODS AND RESULTS: Repetitive reinitiation of bundle branch reentry tachycardia (BBRT), interfascicular tachycardia, or both VTs by ventricular pacing was identified in four ICD patients presenting with VT storm or incessant VT. All patients had a pre-existing prolonged HV interval (75 +/- 9 ms) and left bundle branch block (LBBB) or bifascicular block during sinus rhythm. The VTs included BBRT with LBBB in three patients and interfascicular tachycardia with right bundle branch block (RBBB) and left anterior or left posterior fascicular block in two patients. The paced beats from the ICD electrode exhibited a LBBB pattern of depolarization in two patients and a RBBB contour in V1 and V2 with left axis deviation in two patients. The QRS complex during pacing from the ICD electrode closely resembled that of the recurrent VT in all four patients suggesting that the pacing site of the ICD electrode was in proximity to the myocardial exit site of the bundle fascicle used for antegrade conduction during the reinitiated VT. Ventricular pacing from the ICD electrode after termination of the VT apparently encountered the retrograde refractoriness of this bundle fascicle and allowed immediate re-propagation of the wavefront orthodromically along the VT circuit. BBRT was eliminated by ablation of the right bundle branch. Successful ablation of the interfascicular tachycardias was achieved by targeting (1) an abnormal potential of the distal left posterior Purkinje network or (2) a diastolic potential during VT in the midinferior left ventricular (LV) septum. CONCLUSIONS: Repetitive reinitiation of BBRT and interfascicular tachycardia by ventricular pacing from the ICD electrode should be considered as a mechanism of VT storm refractory to ICD therapy in patients with a pre-existing conduction delay within the His-Purkinje system.