[Bevacizumab/irinotecan. An active treatment for recurrent high grade gliomas: preliminary results of an ANOCEF Multicenter Study]. / Bevacizumab/irinotecan. Un nouveau traitement actif dans les gliomes de haut grade récidivants: résultats préliminaires d'une étude multicentrique de l'Anocef.

RATIONALE: Second-line chemotherapy is disappointing in recurrent high-grade gliomas. Dramatic responses in recurrent high-grade gliomas have been reported in a recent monocentric trial with a novel association combining bevacizumab (anti-VEGF monoclonal antibody agent) and irinitecan. OBJECTIVE: To report the experience of the ANOCEF group (French speaking neuro-oncology association) using the bevacizumab-irinotecan combination in recurrent high-grade gliomas. METHODS: Eight centers were involved in this retrospective multicenter study. Bevacizumab-irinotecan was delivered as previously described in a compassional setting to non-selected patients suffering from a high-grade glioma (WHO grade III and IV). Response rate at two months of the onset of the treatment was analyzed using the Macdonald criteria. The toxicity profile of the treatment was also investigated. RESULTS: From 2006 to 2007, 77 patients were treated (median age: 52 years; median Karnofsky score: 70) for a recurrent high-grade glioma (49 grade IV, 28 grade III). At two months, the response rates were objective response=36% (54% in grade III and 27% in grade IV); stable disease=39%; progressive disease=13%; patients not evaluable because of a rapid fatal clinical deterioration=12%. Improvement was noted in 49% of patients. Among the main toxicities, we noted; intratumoral hemorrage (n=5 with spontaneous regression in three) and thromboembolic complications including venous thrombophlebitis (n=4), pulmonary embolism (n=2), myocardial infarction (n=1), grade III-IV hematotoxicity (n=2), reversible leukoencephalopathy (n=1). CONCLUSION: This retrospective multicenter study adds further arguments in favor of the promising results of this new combination and its potential rapidity of action in recurrent high-grade gliomas. Antiangiogenic agents expose the patients to a well-known risk of thromboembolic and hemorragic complications, necessitating careful follow-up and patient selection in light of the cardiovascular contraindications.

Estimation of distance between a unipolar recording electrode and a myocardial bundle based on signal characteristics.

The aim of the present paper, is the estimation of the distance between an electrode used as a recording site of the extracellular potential field and a surviving myocardial bundle. The importance of the reliable solution of this problem lies among others in controlling ablation. For our purposes one-dimensional propagation is considered and current sources are activated along a cable simulating the propagating waves with constant velocity. Different models of current sources are explored. By use of these models, the corresponding functions expressing extracellular potentials are calculated, using the volume conductor equation. This way, extracellular potentials are modeled as parametric functions of longitudinal distance, while perpendicular distance, current source strength, and other factors related to the propagated wave are parameters of the functions. Simulated annealing is applied for model parameter estimation and appropriate Time Domain and Wavelet Domain cost functions are investigated. Different combinations of model and cost function are evaluated regarding the accuracy of distance estimation. A continuous source model function with a wavelet cost function was found to be the most accurate combination. The accuracy of distance estimation is related to the selected source model and to the actual distance of recording in a nonmonotonic way.

Deconvolution and wavelet-based methods for membrane current estimation from simulated fractionated electrograms.

In infarcted myocardium, extracellular recordings exhibit multiple deflections due to irregular pathway of the electric impulse. In this work the problem of distinguishing local from distant deflections is tackled. In order to evaluate the proposed methods in a controlled setting, simulated data are used, following both Beeler-Reuter and Luo-Rudy kinetics. The input is an array of electrograms positioned on grid-points of a rectangular grid and the output is an array of estimates of the membrane current. First, deconvolution techniques are used in the form of spatial filtering for membrane current estimation from the extracellular recordings. Second, the extracellular recordings undergo wavelet based transformation, followed by a spatial filter which enhances local activity deflections and suppresses distant activity deflections. It is shown that wavelet filtering of the extracellular recordings acts as an evaluator of the efficiency of the deconvolution techniques for the membrane current estimation. Subsequently, activation times based on the results from the two methods are used for the reconstruction of the propagation pattern in a zig-zag case in two-dimensional grids. It is shown that the wavelet-based method is more robust, and can work well even in cases where the grid interval in the y direction is four times larger than the single cell size.

Laplacian electrograms and the interpretation of complex ventricular activation patterns during ventricular fibrillation.

INTRODUCTION: During ventricular fibrillation (VF), interpretation of a local electrogram and determination of the local activation moment are hampered by remote activity or intervening repolarization waves. Successful defibrillation depends on critical timing of the shock relative to local activation. We tested the applicability of Laplacian electrograms for detection of the moment of local activation during VF. METHODS AND RESULTS: From isolated perfused porcine intact hearts, 247 local unipolar electrograms were recorded simultaneously (13 x 19 matrix, interelectrode distance 0.3 mm) from the left ventricular wall during sinus rhythm, following pacing or during VF. Activation maps were constructed based on local unipolar electrograms, and Laplacian electrograms were calculated from local electrograms and its eight neighbors. The Laplacian electrogram displayed a sharp R/S complex with local activation indicated by the moment of zero crossing without interference from remote activity or repolarization waves. Its amplitude increased with decreasing interelectrode distance. Following epicardial stimulation, Laplacian amplitude was significantly larger than during a breakthrough pattern. During VF, identical unipolar electrograms corresponded to Laplacian complexes with different morphology. Collision of wavefronts was associated with entirely positive Laplacian waveforms; "focal" appearance of activity was associated with an entirely negative waveform. Activation block in the activation maps was correlated with the appearance of sustained episodes of negativity or positivity in the Laplacian electrogram (depending on the location of the recording site relative to the line of block). CONCLUSION: Laplacian electrograms allow detection of the moment of local activation without interference from remote activity or repolarization, especially during complex arrhythmias. The technique applied to automatic sensing devices, such as the internal defibrillator, may optimize defibrillation success.

Physicochemical and crystallographic evidence for polymorphism of the racemic ethyl (2-chloromethyl-2,3-dihydro-5H-oxazolo [3, 2-a]pyrimidin-5-one)-6-carboxylate.

The various crystalline forms of an original bicyclic compound [ethyl (2-chloromethyl-2,3-dihydro-5H-oxazolo[3, 2-a]pyrimidin-5-one)-6-carboxylate); EOC] have been obtained and characterized by powder and single-crystal X-ray diffraction, differential scanning calorimetry (DSC), and infrared (IR) and Raman spectroscopy. At 4 degrees C in methanol, a monoclinic racemate (form II) crystallized from the racemic mixture, whereas at 20 degrees C, an orthorhombic racemate (form I) was isolated in trichloroethylene. By increasing the temperature, a solid-solid transition from the stable form II to the stable form I was observed with a Guinier-Simon camera. A I --> II transformation was observed at ambient temperature by DSC.

Spatial filtering methods for local activation determination in fractionated electrograms from simulated infarcted hearts.

The purpose of this work is the enhancement of local activation in multiphasic extracellular recordings coming from infarcted myocardial tissue and, consequently, the distinction of local from distal activation. Deconvolution procedures are applied, in the form of spatial filtering, in order to estimate transmembrane currents from the extracellular recordings. Simulated data are used in order to test the methods. The current source estimates are compared to the actual transmembrane currents and to Laplacian estimates.

Wave propagation simulation in normal and infarcted myocardium: computational and modelling issues.

Simulation of propagating action potentials (PAP) in normal and abnormal myocardium is used for the understanding of mechanisms responsible for eliciting dangerous arrhythmias. One- and two-dimensional models dealing with PAP properties are reviewed in this paper viewed both from the computational and mathematical aspects. These models are used for linking theoretical and experimental results. The discontinuous nature of the PAP is demonstrated through the combination of experimental and theoretically derived results. In particular it can be shown that for increased intracellular coupling resistance the PAP upstroke phase properties (Vmax, dV/dtmax and tau foot) change considerably, and in some cases non-monotonically with increased coupling resistance. It is shown that tau foot) is a parameter that is very sensitive to the cell's distance to the stimulus site, the stimulus strength and the coupling resistance. In particular it can be shown that in a one-dimensional structure the tau foot value can increase dramatically for lower coupling resistance values near the stimulus site and subsequently can be reduced as we move to distances larger than five resting length constants from the stimulus site. The tau foot variability is reduced with increased coupling resistance, rendering the lower coupling resistance structures, under abnormal excitation sequences, more vulnerable to conduction block and arrhythmias. Using the theory of discontinuous propagation of the PAP in the myocardium it is demonstrated that for specific abnormal situations in the myocardium, such as infarcted tissue, one- and two-dimensional models can reliably simulate propagation characteristics and explain complex phenomena such as propagation at bifurcation sites and mechanisms of block and re-entry. In conclusion it is shown that applied mathematics and informatics can help in elucidating electrophysiologically complex mechanisms such as arrhythmias and conduction disturbances in the myocardium.

Effects of intracavitary blood flow and electrode-target distance on radiofrequency power required for transient conduction block in a Langendorff-perfused canine model.

OBJECTIVES: We sought to quantify the effects of electrode-target distance and intracavitary blood flow on radiofrequency (RF) power required to induce transient conduction block, using a Langendorff-perfused canine ablation model. BACKGROUND: Given the thermally mediated nature of RF catheter ablation, cooling effects of intracavitary blood flow and electrode-target distance will influence lesion extension and geometry and electrophysiologic effects. METHODS: In eight Langendorff-perfused canine hearts, the right ventricular free wall was opened, and the right bundle branch (RBB) carefully localized by multielectrode activation mapping. The right atrium was paced at cycle length of 500 ms. Proximal and distal electrodes were attached at the endocardial aspect of the RBB, and the perfused heart was submerged in heparinized blood at 37 degrees C. A standard 4-mm tip ablation electrode was positioned at a constant contact pressure of 5 g between the two electrodes at the site of maximal RBB potential (0 mm) and 2 and 4 mm distant from this site along a line perpendicular to the RBB. RF pulses (500 kHz) were delivered for 30 s at 0.5-W increments until transient bundle branch block. In four hearts, intracavitary flow was simulated by directing a 30-cm/s jet of blood parallel to the septum at the ablation site, and the protocol was repeated to assess the effects on power required for block. In one heart, the effect of variable flow was assessed (0, 15 and 30 cm/s). RESULTS: An exponential distance-related increase was seen in power required for block, from 1.8 +/- 0.9 W (mean +/- SD) at 0 mm to 5.4 +/- 1.1 W at 4 mm. In the presence of 30-cm/s flow, an increase to 3.9 +/- 0.8 W at 0 mm and 13.1 +/- 2.4 W at 2 mm was seen. At 4 mm, coagulum formation invariably occurred before block could be induced. For 15-cm/s flow, less power was required: 3 and 7 W at 0 and 2 mm, respectively. CONCLUSIONS: Increasing the ablation electrode-target distance causes an exponential increase in power required for conduction block; this relation is profoundly influenced by intracavitary flow. Given the geometry of endomyocardial RF lesions, these findings are particularly relevant for directly subendocardial ablation targets.

Increase in hospital admission rates for heart failure in The Netherlands, 1980-1993.

OBJECTIVE: To study the trend in hospital admission rates for heart failure in the Netherlands from 1980 to 1993. DESIGN: All hospital admissions in the Netherlands with a principal discharge diagnosis of heart failure were analysed. In addition, individual records of heart failure patients from a subset of 7 hospitals were analysed to estimate the frequency and timing of readmissions. RESULTS: The total number of discharges for men increased from 7377 in 1980 to 13 022 in 1993, and for women from 7064 to 12 944. From 1980 through 1993 age adjusted discharge rates rose 48% for men and 40% for women. Age adjusted in-hospital mortality for heart failure decreased from 19% in 1980 to 15% in 1993. For all age groups in-hospital mortality for men was higher than for women. The mean length of hospital admissions in 1993 was 14.0 days for men and 16.4 days for women. A review of individual patient records from a 6.3% sample of all hospital admissions in the Netherlands indicated that within a 2 year period 18% of the heart failure patients were admitted more than once and 5% more than twice. CONCLUSIONS: For both men and women a pronounced increase in age adjusted discharge rates for heart failure was observed in the Netherlands from 1980 to 1993. Readmissions were a prominent feature among heart failure patients. Higher survival rates after acute myocardial infarction and the longer survival of patients with heart disease, including heart failure may have contributed to the observed increase. The importance of advances in diagnostic tools and of possible changes in admission policy remain uncertain.

Fractionated electrograms in dilated cardiomyopathy: origin and relation to abnormal conduction.

OBJECTIVES: We sought to investigate the origin of the fractionated electrogram and its relations to abnormal conduction in cardiomyopathic myocardium. BACKGROUND: Patients with dilated cardiomyopathy have a high incidence of ventricular tachycardias. Electrograms recorded in these patients are often fractionated. METHODS: High resolution mapping (200-microM interelectrode distance) of the electrical activity was carried out in 11 superfused papillary muscles and 6 trabeculae from 7 patients who underwent heart transplantation because of dilated cardiomyopathy. Similar measurements were taken in four papillary muscles from dog hearts in which electrical barriers had been artificially made. Ten human preparations were studied histologically. RESULTS: All preparations revealed sites with fractionated electrograms. In three human preparations, activation patterns showed a discernible line of activation block running parallel to the fiber direction. Fractionated electrograms were recorded at sites contiguous to the line of block. In five preparations, fractionated electrograms were recorded at sites where lines of block were not identified. In these preparations, electrical barriers consisted of short stretches of fibrous tissue. In the remaining nine preparations, fractionated electrograms were recorded, both from sites contiguous to distinct obstacles and sites without evidence of a barrier. CONCLUSIONS: Our observations showed that fractionated electrograms recorded in myocardium damaged by cardiomyopathy were due to both distinct, long strands and short stretches of fibrous tissue. Delayed conduction was caused by curvation of activation around the distinct lines of block and by the wavy course of activation between the short barriers. The latter reflects extreme nonuniform anisotropy.

Cost-effectiveness of implantable defibrillator as first-choice therapy versus electrophysiologically guided, tiered strategy in postinfarct sudden death survivors. A randomized study.

BACKGROUND: Rising costs of health care, partly as a result of costly therapeutic innovations, are of concern to both the medical profession and healthcare authorities. The implantable cardioverter-defibrillator (ICD) is still not remunerated by Dutch healthcare insurers. The aim of this study was to evaluate the cost-effectiveness of early implantation of the ICD in postinfarct sudden death survivors. METHODS AND RESULTS: Sixty consecutive postinfarct survivors of cardiac arrest caused by ventricular tachycardia or fibrillation were randomly assigned either ICD as first choice (n = 29) or a tiered therapy starting with antiarrhythmic drugs and guided by electrophysiological (EP) testing (n = 31). Median follow-up was 729 days (range, 3 to 1675 days). Fifteen patients died, 4 in the early ICD group and 11 in the EP-guided strategy group (P = .07). For quantitative assessment, the cost-effectiveness ratio was calculated for both groups and expressed as median total costs per patient per day alive. Because effectiveness aspects other than mortality are not incorporated in this ratio, other factors related to quality of life were used as qualitative measures of cost-effectiveness. The cost-effectiveness ratios were $63 and $94 for the early ICD and EP-guided strategy groups, respectively, per patient per day alive. This amounts to a net cost-effectiveness of $11,315 per patient per year alive saved by early ICD implantation. Costs in the early ICD group were higher only during the first 3 months of follow-up, but as a result of the high proportion of therapy changes, including arrhythmia surgery and late ICD implantation, costs in the EP-guided strategy group became higher after that. Patients discharged with antiarrhythmic drugs as sole therapy had the lowest total costs. This subset, however, showed extremely high mortality, resulting in a poor cost-effectiveness ratio ($196 per day). Invasive therapies and hospitalization were the major contributors to costs. If quality-of-life measures are taken into account, the cost-effectiveness of early ICD implantation was even more favorable. Recurrent cardiac arrest and cardiac transplantation occurred in the EP-guided strategy group only, whereas exercise tolerance, total hospitalization duration, number of invasive procedures, and antiarrhythmic therapy changes were significantly in favor of early ICD implantation. CONCLUSIONS: In terms of cost-effectiveness, early ICD implantation is superior to the EP-guided therapeutic strategy in postinfarct sudden death survivors.

Activation delay in healed myocardial infarction: a comparison between model and experiment.

Conduction delay in healed myocardial infarction, facilitating reentry, is frequently based on an increased path length the activation has to travel in a matrix of merging and diverging bundles that survive in the infarcted area. Additional delay occurs at sites where bundles bifurcate. The purpose of this study was to investigate conduction delay at sites where bundles bifurcate. A computer model was developed to simulate spread of activation in a two-dimensional sheet of excitable elements. A structure consisting of two isolated bundles merging into a single one was modeled. Extracellular electrograms calculated in the model were comparable to electrograms obtained in a superfused infarcted papillary muscle model. A zone of crowded isochrones or local conduction delay was found at the site where an isolated bundle bifurcated. The position of the isochrones in this area depended on the way activation times were determined. Lines of activation delay were mainly perpendicular to the fiber direction. In conclusion, the results have enabled us to better understand extracellular electrograms at pivoting points and show that activation sequences at a microscopic level can best be constructed on the basis of Laplacian signals.

Dispersion of 'refractoriness' in noninfarcted myocardium of patients with ventricular tachycardia or ventricular fibrillation after myocardial infarction.

BACKGROUND: Postinfarction ventricular tachycardias (VTs) may degenerate into ventricular fibrillation (VF), but this does not happen in all patients. The underlying mechanism is not exactly known, but dispersion of refractory periods is considered a major factor in both induction and persistence of reentrant arrhythmias in general. Hypertrophied, noninfarcted myocardium has altered electrophysiological characteristics. We hypothesized that noninfarcted ventricular tissue may provide the heterogeneities that cause the transition from VT into VF. Local fibrillation intervals, ie, the average interval between local activations during VF, have previously been shown to correlate well with local refractoriness in human and canine atrium and in porcine and canine ventricle and may therefore be used as an index of local refractoriness. This technique permits simultaneous assessment of refractoriness at multiple sites. METHODS AND RESULTS: We measured local fibrillation intervals at 32 to 64 sites in the noninfarcted part of the left ventricle in patients undergoing antiarrhythmic surgery for symptomatic, drug-refractory, postinfarction ventricular tachyarrhythmias. The grid of electrodes (interelectrode distance, 7 mm) was attached to the epicardium of the left ventricle remote from the infarcted tissue. Group 1 consisted of 7 patients with hemodynamically tolerable sustained VT (VT group). Group 2 consisted of 7 patients with cardiac arrest and documented VF (VF group). With the patients on cardiopulmonary bypass, VF was induced by multiple premature stimulation. The VF interval was not significantly different in the two study groups (VT group, 136 +/- 5.5 ms; VF group, 129 +/- 3.4 ms, mean +/- SEM). However, spatial dispersion of the VF intervals (remote from the infarcted area) expressed as the coefficient of variation of VF intervals (SD x 100/mean VF interval in each heart) was significantly larger in the VF group. It was 3.63 +/- 0.56 in the VF group and 1.55 +/- 0.40 in the VT group (mean +/- SEM; P < .01). Differences between the shortest and longest VF intervals in one and the same heart and the largest difference between two adjacent sites were also larger in the VF group (P < .02 and P < .05, respectively). CONCLUSIONS: This study shows larger dispersion in VF intervals and therefore suggests larger dispersion of refractory periods in parts of the myocardium remote from the infarction in patients with postinfarction VF than in patients with postinfarction VT.

Randomized study of implantable defibrillator as first-choice therapy versus conventional strategy in postinfarct sudden death survivors.

BACKGROUND: In retrospective studies of sudden cardiac death survivors, the implantable cardioverter-defibrillator (ICD) compares favorably with medical and surgical therapy. Thus, use of the conventional strategy of starting treatment with antiarrhythmic drugs (AD), at least in certain patient categories, may be questionable. The goal of this study was to analyze the effectiveness of ICD implantation as first-choice therapy versus the conventional therapeutic strategy of starting with AD. METHODS AND RESULTS: Sixty consecutive survivors of cardiac arrest caused by old myocardial infarction were randomly assigned early ICD implantation (n = 29) or conventional therapy (n = 31). Baseline characteristics were similar in the two groups. Therapy in each patient was always guided by ECG monitoring, exercise testing, and programmed electrical stimulation (PES). Primary end points (main outcome events, including death, recurrent cardiac arrest, and cardiac transplantation), number of invasive procedures and antiarrhythmic therapy changes, and duration of hospitalization were compared. Median follow-up was 24 months (mean, 27 months). In the early ICD group, 4 patients (14%) died, all of cardiac causes. In the conventional group, 20 patients failed AD and subsequently underwent map-guided ventricular tachycardia (VT) surgery (6 patients) or ICD implantation (14 patients). Of the 6 VT surgery patients, 1 died, 1 had cardiac transplantation, and 1 had an ICD implantation because of persistent inducibility despite the addition of AD. Of the 11 patients who remained on AD as sole therapy, 2 died in the hospital before they could be retested by PES, leaving 9, judged adequately protected by AD alone. Of those, 5 died, and 1 survived recurrent cardiac arrest followed by ICD implantation. In total, 16 conventionally treated patients ended up with late ICD implantation, 3 of whom died. Thus, total mortality in the conventional group was 11 patients (35%): 4 died suddenly, 5 died of heart failure, and 2 died of noncardiac causes. Comparison of the main outcome events in both strategies showed a significant difference in favor of early ICD implantation (hazard ratio, 0.27; 95% CI, 0.09 to 0.85; P = .02). In addition, the early ICD group underwent fewer invasive procedures (median, 1 versus 3; P < .0001), had less therapy changes (P < .0001), and spent fewer days in hospital (median, 34 versus 49; P = .02). CONCLUSIONS: These data suggest that ICD implantation as first choice is preferable to the conventional approach in survivors of cardiac arrest caused by old myocardial infarction. Conventionally treated patients are likely to end up with an ICD, and those who remain on AD as sole therapy have a high risk of death regardless of efficacy assessment, including PES.

Effects of barriers on propagation of action potentials in two-dimensional cardiac tissue. A computer simulation study.

A two-dimensional anisotropic model of cardiac ventricular muscle was used to study the effects of discontinuities (barriers), such as dead cells or high-resistance areas, on longitudinal plane-wave propagation. Problems in propagation appear when long barriers become thicker and their spacing closer. Short barriers with large widths and small spacing also cause propagation disturbances and significant delays in their vicinity. If the plane wave front propagates through the barriers, the velocity returns to near normal within one-length constant away from the end of the barrier region. For a funnel-like structure, an opening of 13 cells should exist for longitudinal plane wave propagation. For smaller openings, the ratio of openings required for propagation to occur when traveling from a narrow to a wider area of tissue is proportional to the anisotropy ratio, which can cause unidirectional block. Tortuosity, created by spatial distribution of dead cell barriers, can facilitate propagation by changing the effective impedance the wave front sees, and can create multiple local delays, which may result in discrepancies when measuring propagation velocity.

[Increase in the number of admissions due to heart failure in Dutch hospitals in the period 1980-1992]. / Stijging van het aantal opnamen wegens hartfalen in Nederlandse ziekenhuizen in de periode 1980-1992.

OBJECTIVE: Determination of the trend in the occurrence of hospital admissions because of heart failure in the Netherlands. DESIGN: Descriptive investigation. SETTING: Dutch general and university hospitals. METHOD: Data on hospital admissions because of heart failure from 1980 to 1992, obtained from the National Medical Register, were analysed. Three ICD-9 CM diagnoses were combined (congestive heart failure 428.x, diseases of the heart due to hypertension 402.x and myocardial degeneration 429.I). RESULTS: From 1980 through 1992 the annual number of hospital admissions for heart failure increased by 69%, for both men and women, from 14,441 to 24,368. Age-adjusted admission rates increased by 43% for men, and by 30% for women. The admission rates were strongly age-related, with higher rates in the older age groups. Among men 89% of the patients in 1992 were older than 60 years, and 63% older than 70 years. Among women these figures were 94% and 79%, respectively. During the study period the age-specific admission rates rose in all relevant age groups. The rise was higher in the older age groups. In 1992 the average duration of stay in hospital was 14 days for men and 17 for women. CONCLUSION: Probable causes of the rise in the number of hospital admissions for heart failure were the increasing median age of the population, higher survival rates after acute myocardial infarction and longer survival of persons with heart disease. Demographic changes and medical progress will probably lead to a further rise in morbidity and mortality and of costs of heart failure.

Dispersion of refractoriness in normal and ischaemic canine ventricle: effects of sympathetic stimulation.

OBJECTIVE: Dispersion in refractoriness is considered a major factor in induction and persistence of cardiac arrhythmias. The sympathetic nervous system is known to modulate refractoriness. An index of refractoriness has therefore been assessed in normal and ischaemic myocardium simultaneously at multiple sites, with and without sympathetic stimulation. METHODS: In six dogs on total cardiopulmonary bypass the average interval between local activations was measured during artificially induced ventricular fibrillation from extracellular electrograms simultaneously recorded from 32 ventricular sites. These local ventricular fibrillation intervals may be used as an index of local refractoriness. RESULTS: During regional ischaemia, ventricular fibrillation intervals of ischaemic sites could prolong by up to 60% after 3 min following coronary occlusion. Left stellate ganglion stimulation during ischaemia produced either no response or prolonged the ventricular fibrillation intervals even further at ischaemic sites, whereas ventricular fibrillation intervals at non-ischaemic sites shortened. Dispersion in refractoriness across the ischaemic border increased by 14-59% in individual hearts following sympathetic stimulation during acute, regional ischaemia. CONCLUSIONS: Due to opposite effects on normal and ischaemic myocardium, sympathetic stimulation increases the difference in refractoriness over the ischaemic border. This may enhance the chance for regional conduction block and the propensity to re-entrant arrhythmias.

Slow conduction in the infarcted human heart. 'Zigzag' course of activation.

BACKGROUND: Ventricular tachycardias occurring in the chronic phase of myocardial infarction are caused by reentry. Areas of slow conduction, facilitating reentry, are often found in the infarcted zone. The purpose of this study was to elucidate the mechanism of slow conduction in the chronic infarcted human heart. METHODS AND RESULTS: Spread of activation was studied in infarcted papillary muscles from hearts of patients who underwent heart transplantation because of infarction. Recordings were carried out on 10 papillary muscles that were superfused in a tissue bath. High-resolution mapping was performed in areas revealing slow conduction. Activation delay between sites perpendicular to the fiber direction and 1.4 mm apart could be as long as 45 milliseconds. Analysis of activation times revealed that activation spread in tracts parallel to the fiber direction. Conduction velocity in the tracts was between 0.6 and 1 m/s. Although tracts were separated from each other over distances up to 8 mm, they often connected with each other at one or more sites, forming a complex network of connected tracts. In this network, wave fronts could travel perpendicular to the fiber direction. Separation of tracts was due to collagenous septa. At sites where tracts were interconnected, the collagenous barriers were interrupted. CONCLUSIONS: Slow conduction perpendicular to the fiber direction in infarcted myocardial tissue is caused by a "zigzag" course of activation at high speed. Activation proceeds along pathways lengthened by branching and merging bundles of surviving myocytes ensheathed by collagenous septa.

Interaction of sympathetic and parasympathetic nervous system on ventricular refractoriness assessed by local fibrillation intervals in the canine heart.

OBJECTIVE: The aim was to assess the effects of autonomic nerve stimulation on local ventricular refractoriness by measuring local ventricular fibrillation intervals. METHODS: In 10 dogs on cardiopulmonary bypass, ventricular fibrillation intervals were recorded simultaneously at up to 32 sites before and after neural stimulation. In four dogs (group 1) the response to bilateral stellate ganglion stimulation was measured before and after bilateral cervical vagotomy. In three dogs (group 2) bilateral stellate ganglion stimulation, vagal nerve stimulation, and combined vagal and stellate ganglia stimulation were performed. In three dogs (group 3) the same protocol was applied after total decentralisation of the autonomic nervous system. RESULTS: Bilateral stellate ganglion stimulation shortened the ventricular fibrillation interval at 44-50% of myocardial sites before and after vagotomy, whereas prolongation of the interval was observed at 14-18% of the sites. At higher stimulus strength shortening of the interval was measured at 85% of the sites in the intact and decentralised groups. No prolongation was observed. The shortening was largest in the decentralised group (11.1 ms). Dispersion in refractoriness increased in hearts from all groups, but not in each individual heart. Left, right, or bilateral vagal stimulation was without effect at about 75% of the tested sites. The fact that the response to autonomic nerve stimulation varies from site to site warrants our approach of simultaneous recordings at multiple sites. Dispersion in refractoriness was not affected by vagal stimulation. Combined autonomic stimulation had approximately the same effect on dispersion in refractoriness as bilateral stellate ganglion stimulation alone. However, vagal stimulation attenuated the responses to bilateral stellate ganglion stimulation by some 20% in the decentralised group. CONCLUSIONS: Vagal stimulation has minor effects on ventricular refractoriness, but this is not due to sparse innervation, since vagal stimulation is able to mitigate the effects of sympathetic stimulation in decentralised hearts.

Increased dispersion of "refractoriness" in patients with idiopathic paroxysmal atrial fibrillation.

The average interval between local depolarizations during atrial fibrillation, the so-called atrial fibrillation interval, was used as an index for local "refractoriness." This was based on the assumption that during fibrillation, cells are reexcited as soon as their refractory period ends. A very good correlation was found between refractory periods determined with the extrastimulus technique at a basic cycle length of 400 ms and atrial fibrillation intervals measured at the same epicardial sites of the right atrium. This new technique was used to assess dispersion in atrial fibrillation intervals in 10 patients with idiopathic paroxysmal atrial fibrillation and in a control group of 6 patients who were undergoing cardiac surgery. After a routine median sternotomy a multiterminal grid with up to 40 electrodes was placed over the right atrium, and atrial fibrillation was induced by premature stimulation. The average fibrillation interval in the test group, recorded at 247 sites, was 152 +/- 3 ms and that in the control group, recorded at 118 sites, was 176 +/- 8.1 ms (p less than 0.05). Dispersion in atrial fibrillation intervals, defined as the variance of the fibrillation intervals at all the recording sites, was three times larger in the group with paroxysmal atrial fibrillation than in the control group. This study suggests that both a shorter refractory period and a larger dispersion in refractoriness are responsible for the recurrence of atrial fibrillation.