In isolated superfused left atria of the rabbit, inhomogeneity in conduction was quantified using the activation times measured with a high-density mapping system. At each recording site, the maximal difference with neighboring activation times (i.e., phase difference) was calculated. Local phase differences were plotted in a phase map, revealing the spatial distribution of inhomogeneities in conduction, and from each map a total index of inhomogeneity was calculated. During slow pacing (2 Hz) local differences in conduction velocity, depending on the direction of propagation, were found already. Inhomogeneity in conduction increased significantly during single early premature beats (inhomogeneity index increased from 2.3 to 3.1; P less than 0.001). The application of multiple premature beats further increased inhomogeneity in conduction, whereas rapid pacing induced the highest level of inhomogeneity (inhomogeneity index 5.3; P less than 0.001). An analysis of the spatial distribution of maximal phase differences revealed that during premature beats inhomogeneities in conduction were limited to an area of 6 mm around the point of origin of the premature impulse, whereas during rapid pacing inhomogeneities in conduction were found throughout the whole preparation. Phase maps constructed during the initiation of reentrant tachyarrhythmias showed that reentry occurred at sites with the highest phase differences. Quantification of spatial inhomogeneities in conduction is a useful tool to evaluate the vulnerability of the myocardial substrate for reentrant arrhythmias.

In the isolated blood-perfused canine heart we produced episodes of rapid atrial flutter by continuous infusion of acetylcholine and rapid pacing. The spread of excitation during atrial flutter was mapped with the aid of two endocavitary mapping electrodes containing 960 leads and recording from 192 different sites simultaneously. The flutter maps clearly showed that intra-atrial reentry was the mechanism responsible for the arrhythmia. However, the localization and size of the intra-atrial circuits differed from case to case even in the same heart. The orifices of the venae cavae or the atrioventricular ring did not serve as a central anatomic obstacle for circus movement. We also failed to identify a special role of the intemodal pathways in the formation of the loop. Instead, the intra-atrial circuits could be found everywhere, provided sufficient atrial mass was available to accommodate the circuit. The diameter of the circuits varied between 1.5 and 3 cm at a cycle length between 65 and 155 msec. The average conduction velocity of the circulating impulse varied between 60 and 80 cm/sec. Spontaneous termination of atrial flutter frequently occurred and was based on local conduction block in a narrow part of the circuit. Another interesting aspect of these studies is the finding that during continuous circus movement of the impulse, the amount of myocardium that is activated may vary considerably. This marked periodicity in excited tissue mass during atrial flutter could adequately explain the continuously undulating baseline or typical sawtoothlike F waves as seen in the surface electrocardiogram during atrial flutter. Circulation 70, No. 1, 123-135, 1984. THE EXACT MECHANISMS underlying atrial flutter in human beings are still unknown. Detailed clinical studies with intracavitary and intraesophageal leads and programmed electrical stimulation have not resulted in the identification of a single mechanism of human atrial flutter. The results of some studies were explained by assuming the presence of an ectopic focus of abnormal impulse formation, -5 whereas other investigations point to a circus movement involving a large part of the atria.3' 61 Extensive epicardial mapping of the atria in patients with atnal flutter who are subjected to cardiac surgery could be an excellent and direct way to evaluate this condition. However, such studies have been scarce and do not yet allow general conclusions. 12

Detailed spatial analysis of propagation of individual action potential was performed during spontaneous bursts of activity in the isolated 17-day pregnant rat myometrium. Use was made of high-resolution mapping with simultaneous recordings from 240 extracellular electrodes. Positioning of the electrode assembly by itself did not have any adverse effects, and no differences were found in the period or duration of spontaneous bursts recorded with and without the electrode assembly touching the tissue. The spread of propagation of individual action potentials was reconstructed at several moments during myometrial spike bursts. Both the direction and the sequence of activation of the myometrium were found to be highly variable and depended on 1) the level and spatial dispersion of excitability and 2) whether conduction occurred predominantly in the longitudinal or the circumferential direction. Furthermore, conduction was frequently complicated by the spontaneous occurrence of 1) lines of conduction block, 2) focal sites of pacemaking, or 3) merging of two or more wavelets into a single wave. In contrast, when the myometrium was divided into small segments, activity became much more regular, and both the location of the pacemaker and the direction of propagation were much more stable than in the whole myometrium. In conclusion, spontaneous spatial variations in local spike propagation at the preterm stage could provide for the necessary asynchrony in activation and play a role in the prevention of forceful contractions and premature labor.

INTRODUCTION: In primary biliary cholangitis (PBC), bilirubin and alkaline phosphatase (ALP) are widely established as independent predictors of prognosis. Current treatment goals do not aim for normalization of surrogate markers because their association with survival has not been defined. METHODS: The patient cohort from the GLOBAL PBC Study Group was used, comprising of long-term follow-up data from European and North American centers. Ursodeoxycholic acid-treated and untreated patients with bilirubin levels ≤1 × upper limit of normal (ULN) at baseline or 1 year were included. The association of normal ALP with transplant-free survival was assessed in a subgroup with ALP ≤1.67 × ULN at 1 year. Optimal thresholds of bilirubin and ALP to predict liver transplantation (LT) or death were evaluated. RESULTS: There were 2,281 patients included in the time zero cohort and 2,555 patients in the 1-year cohort. The bilirubin threshold with the highest ability to predict LT or death at 1 year was 0.6 × ULN (hazard ratio 2.12, 95% CI 1.69–2.66, P < 0.001). The 10-year survival rates of patients with bilirubin ≤0.6 × ULN and >0.6 × ULN were 91.3% and 79.2%, respectively (P < 0.001). The risk for LT or death was stable below the bilirubin levels of 0.6 × ULN, yet increased beyond this threshold. Ursodeoxycholic acid-induced reduction in bilirubin below this threshold was associated with an 11% improvement in 10-year survival. Furthermore, ALP normalization was optimal, with 10-year survival rates of 93.2% in patients with ALP ≤ 1 × ULN and 86.1% in those with ALP 1.0–1.67 × ULN. DISCUSSION: Attaining bilirubin levels ≤0.6 × ULN or normal ALP are associated with the lowest risk for LT or death in patients with PBC. This has important implications for treatment targets.

Summary Background Fibrosis stage predicts prognosis in patients with chronic liver disease independent of aetiology, although its precise role in risk stratification in patients with primary biliary cholangitis (PBC) remains undefined. Aim To assess the utility of baseline fibrosis stage in predicting long‐term outcomes in the context of biochemical risk stratification Methods In a large and globally representative cohort of patients with PBC, liver biopsies performed from 1980 to 2014 were evaluated. The predictive ability of histologic fibrosis stage in addition to treatment response at 1 year (Toronto/Paris‐II criteria), as well as non‐invasive markers of fibrosis (AST/ALT ratio [AAR], AST to platelet ratio index [APRI], FIB‐4), for transplant‐free survival was assessed with Cox proportional‐hazards models. Results There were 1828 patients with baseline liver biopsy. Advanced histologic fibrosis (stage 3/4) was an independent predictor of survival in addition to non‐invasive measures of fibrosis with the hazard ratios ranging from 1.59 to 2.73 (P < .001). Patients with advanced histologic fibrosis stage had worse survival despite biochemical treatment response, with a 10‐year survival of 76.0%‐86.6% compared to 94.5%‐95.1% depending on the treatment response criteria used. Poor correlations were observed between non‐invasive measures of fibrosis and histologic fibrosis stage. Conclusion Assessment of fibrosis stage grants prognostic value beyond biochemical treatment response at 1 year. This highlights the need to incorporate fibrosis stage in individual risk stratification in patients with PBC, partly to identify those that may derive benefit from novel therapies.