Clinical phenotypes and therapeutic responses in cutaneous-predominant sarcoidosis: 6-year experience in a tertiary referral service.

BACKGROUND: There is a limited evidence base for the treatment of cutaneous sarcoidosis. OBJECTIVE: To describe treatment modalities and responses in patients with predominantly cutaneous sarcoidosis, in addition to clinical characteristics and prevalence of systemic disease. METHODS: Data were prospectively collected over a 6-year period. The Cutaneous Sarcoidosis Activity and Morphology Index was used to assess treatment effectiveness. RESULTS: In total, 47 patients with biopsy-confirmed cutaneous sarcoidosis were identified. Morphologically, the most common lesions were papules (49%) and plaques (42.6%). The most commonly affected sites were the head and neck (79%); 89.4% had systemic as well as cutaneous disease; 77% received systemic corticosteroid therapy, while 87% required further steroid-sparing treatment; 40% achieved clinical remission with hydroxychloroquine (HCQ) and 88% achieved clinical remission with methotrexate (MTX). OR of achieving remission on MTX compared with HCQ was 9.8 (95% CI 2.4-40.4, P = 0.001). MTX was superior to both azathioprine (AZA) (OR = 22; 95% CI 1.7-285.9; P = 0.02) and mycophenolate mofetil (MMF) (OR = 22; 95% CI 1.7-285.9; P = 0.02) in achieving remission. CONCLUSION: HCQ is effective and well-tolerated. MTX was associated with significantly increased probability of achieving clinical remission compared with AZA and MMF.

Gentamicin induced ototoxicity during treatment of enterococcal endocarditis: resolution with substitution by netilmicin.

Enterococcal endocarditis can be very difficult to eradicate, requiring prolonged treatment with a combination of a penicillin and an aminoglycoside. In this patient with a pacemaker associated enterococcal endocarditis, ototoxicity occurred due to total gentamicin dose despite plasma concentrations consistently within the treatment range. Substitution with netilmicin, without a break in aminoglycoside treatment, resulted in a rapid improvement in hearing and allowed the required course of aminoglycoside to be completed. The risk factors for ototoxicity with gentamicin are reviewed, in particular the dangers of increasing age and of multiple and prolonged courses. Close treatment monitoring does not totally avoid this risk, especially when prolonged aminoglycoside treatment is required. This case emphasises the need for prompt investigation and adequate, definitive treatment of enterococcal endocarditis to avoid the increased risk consequent on repeated courses of antibiotics. The resolution of the ototoxicity with netilmicin is consistent with other reports of lower cochleotoxicity than with other aminoglycosides.

The role of atrial ectopics in initiating paroxysmal atrial fibrillation.

AIMS: To characterize the nature and timing of atrial ectopics preceding clinical episodes of paroxysmal atrial fibrillation. METHODS AND RESULTS: Holter recordings (n= 177, 60 patients, 58% male, mean age 61.7 +/- 11.5 years) were performed on patients with paroxysmal atrial fibrillation. These were subjected to standard analysis and recordings containing atrial fibrillation episodes suitable for analysis were identified (n = 74). Beat interval files differentiating sinus rhythm from atrial fibrillation were generated and atrial ectopics were identified. Atrial ectopics preceding atrial fibrillation were found to be more frequent (5.07 +/- 7.39 min(-1)) and more premature (ratio of coupling interval to that of surrounding sinus cycles = 0.56 +/- 0.08) compared to ectopics occurring remote from atrial fibrillation episodes (frequency = 3.60 +/- 7.32 min(-1) P = 5 x 10(-24), prematurity ratio = 0.60 +/- 0.10, P = 2 x 10(-73)). Atrial ectopic coupling interval frequency histograms were generated and analysed visually and by an automated statistically based test. Many ectopics were seen to occur at one coupling interval in 27 recordings (in eight this occurred only preceding atrial fibrillation onset, while in a further 19 cases this was also seen remote from atrial fibrillation onset). Overall 45% of ectopics preceding atrial fibrillation episodes occurred in isolation, 13% as part of a bigeminal rhythm, 22% as couplets and 20% as runs. This pattern did not differ from that seen remote from atrial fibrillation episodes. CONCLUSION: Paroxysmal atrial fibrillation is preceded by ectopics of a fixed coupling interval in a significant proportion of patients. If, as seems likely, this is a marker of 'focally mediated' atrial fibrillation, then Holter techniques may provide a useful screening tool with which to identify patients suitable for fuller electrophysiological assessment.

Non-pharmacological treatments for atrial fibrillation. A critical perspective on the status quo.

In a proportion of patients with atrial fibrillation, antiarrhythmic drugs are either ineffective, unsafe, or poorly tolerated. Accordingly, a variety of non-pharmacological treatments have been developed. This article critically reviews these modalities. (i) For ventricular rate control, catheter ablation of the atrioventricular node with pacemaker implantation is commonplace. An alternative is atrioventricular node modulation using a procedure similar to "slow pathway" ablation. (ii) For restoration of sinus rhythm, internal cardioversion using low energy shocks is highly effective; this has prompted the development of atrial and dual chamber defibrillators. (iii) To eliminate the atrial fibrillation substrate, a number of surgical procedures have been developed, of which the most effective is the "Maze" operation. The efficacy of this operation cannot be reproduced by conventional catheter ablation, and current research is concentrating on simplified procedures using new catheter designs for linear ablation. (iv) Finally, pacemakers and catheter ablation may be used to suppress the triggers for atrial fibrillation episodes. A number of atrial algorithms are under investigation for overdrive suppression of ectopy, and the use of multisite atrial pacing to alter the atrial response to ectopy has shown promising results. Catheter ablation has shown considerable success in preventing "focal" atrial fibrillation that is triggered or driven by ectopy arising usually from the pulmonary veins. To date, there are few data regarding the long-term efficacy and safety of these techniques, and their effects on quality of life. However, ongoing multicentre trials addressing these issues are expected to report over the next few years.

Unipolar electrogram characteristics predictive of successful radiofrequency catheter ablation of accessory pathways.

INTRODUCTION: The purpose of this study was to determine the characteristics of the unipolar electrogram that are most helpful in predicting successful radiofrequency ablation of accessory pathways. METHODS AND RESULTS: The unipolar electrogram was analyzed at 185 ablation sites in 53 patients; 94 attempts were directed at the site of earliest atrial activation ("atrial group") and 91 at the site of earliest ventricular activation ("ventricular group"). The electrogram was analyzed for several features, including pattern ("QS" or "initial R"). Unipolar pattern: Overall, a "QS" pattern was seen at 55% of unsuccessful, 75% of temporarily successful, and 90% of permanently successful sites. For the atrial group, the respective frequencies were 53%, 77%, and 92%, and for the ventricular group, 57%, 73%, and 86%. The difference in pattern distribution between unsuccessful and permanently successful sites was significant for all groups: overall, P < 0.0001; atrial group, P = 0.0005; ventricular group, P = 0.02. Absence of a "QS" pattern (i.e., "initial R") predicted a 92% chance of unsuccessful ablation. Additional features: Activation times were significantly shorter at permanently successful than at unsuccessful (P < 0.0001) or temporarily successful sites (P = 0.0002). No significant differences were found in atrial or ventricular amplitudes or in A/V ratios. Intrinsic deflection slew was lower at temporarily successful sites (P = 0.03 vs all other sites). CONCLUSION: Ablation at sites revealing an "initial R" pattern (i.e., absent "QS") is very unlikely to be successful. Activation time is shorter at successful sites. These features are equally applicable when mapping the atrial potential as when mapping the ventricular potential.

Double-blind placebo-controlled trial of digoxin in symptomatic paroxysmal atrial fibrillation.

BACKGROUND: Digoxin is commonly prescribed in symptomatic paroxysmal atrial fibrillation (AF) but has never been evaluated in this condition. METHODS AND RESULTS: From a multicenter registry, 43 representative patients with frequent symptomatic AF episodes were recruited into a randomized, double-blind crossover comparison of digoxin (serum concentration, 1.29+/-0.35 nmol/L) and placebo. The study end point was the occurrence of 2 AF episodes (documented by patient-activated monitors), censored at 61 days. The median time to 2 episodes was 13.5 days on placebo and 18.7 days on digoxin (P<0. 05). The relative risk (95% CI) of 2 episodes (placebo:digoxin) was 2.19 (1.07 to 4.50). A similar effect was seen on the median time to 1 episode: increased from 3.5 to 5.4 days (P<0.05), relative risk 1. 69 (0.88 to 3.24). The mean+/-SD ventricular rates during AF recordings during placebo and digoxin treatment were 138+/-32 and 125+/-35 bpm, respectively (P<0.01). Twenty-four-hour ambulatory ECG recordings did not show significant differences in the frequency or duration of AF or in ventricular rate. CONCLUSIONS: Digoxin reduces the frequency of symptomatic AF episodes. However, the estimated effect is small and may be due to a reduction in the ventricular rate or irregularity rather than an antiarrhythmic action.

Circadian variation in atrial fibrillation in patients with frequent paroxysms.

Determinants of the duration of episodes of atrial fibrillation (AF) in patients with paroxysmal atrial fibrillation (PAF) are poorly understood. However, autonomic tone shows circadian variation and is known to affect atrial electrophysiology. We therefore compared the duration of episodes of AF with an onset during the day (08:00-22:00) to those with an onset during the night in a database of 24-hour ECG recordings in patients with frequent symptomatic PAF. The heart rate in the 30 seconds prior to AF onset was also compared. From 42 recordings, 296 episodes of AF > 30 seconds duration and preceded by > 60 seconds sinus rhythm were identified. The 165 nocturnal episodes tended to be shorter (median = 1.15 min) than the 131 diurnal episodes (median = 1.5 min) and the distribution of nocturnal and diurnal durations was significantly different (P = 0.007; Kolgomorov-Smirnov test). This was also true in recordings containing at least 1 diurnal and at least 1 nocturnal episode. The mean heart rate prior to AF onset was lower at night (62.2 +/- 11.8 vs 75.6 +/- 16.4 beats/min; P < 0.0001 Wilcoxon test). These findings suggest that in patients with frequent symptomatic PAF, autonomic influences affect the duration of episodes of AF and has pathphysiological and therapeutic implications.

Age and gender influences on rate and duration of paroxysmal atrial fibrillation.

UNLABELLED: The influence of age and gender on the character of paroxysmal atrial fibrillation (PAD) has not been described. METHODS: The heart rate (HR) during PAF in patients receiving placebo or antiarrhythmic therapy was analyzed. Data from 177 24-hour Holter recordings were analyzed to mark the onset and termination of PAF and converted into RR interval files. PAF episodes lasting at least 2 minutes and containing < or = 20% noise were included. HR during the first 30-second segment versus during the remainder of the episode, and the duration of PAF episodes were compared among groups of different ages and sex (Wilcoxon test). RESULTS: 236 episodes from 55 recordings in 32 patients (all patients: 61.4 +/- 12.8 years; men (19): 58.5 +/- 12.6 years; women (13) 65.5 +/- 12.4 years, P = ns for difference in age) fulfilled the inclusion criteria. Women had a higher mean heart rate at AF onset (123 +/- 35 beats/min vs 115 +/- 20 beats/min, P = 0.02) and during the remainder of the episode (120 +/- 25 beats/min vs 112 +/- 22 beats/min at the start, P = 0.01, and 116 +/- 26 beats/min vs 108 +/- 18 beats/min subsequently, P = 0.01). Episodes tended to be longer in women (mean 89.8 min vs 50.5 min, P = NS) and in the aged (mean 83.8 min vs 46.9 min, P = NS). CONCLUSION: PAF episodes are associated with faster heart rates and last longer in women, which may reflect differing autonomic responses to AF. A slower ventricular rate during PAF in older patients probably reflects an increasing prevalence of impaired atrioventricular conduction.

Evolution of changes in the ventricular rhythm during paroxysmal atrial fibrillation.

Changes in the RR interval within episodes of paroxysmal atrial fibrillation (PAF) have not been fully characterized. A database of 177 24-hour Holter recordings were created from patients with PAF in the CRAFT studies. PAF episodes of > or = 1 minute duration containing < or = 20% noise and preceded by > or = 1 minute of sinus rhythm with < or = 20% noise were selected. Sections of each AF episode containing 10 and 25 RR intervals were identified at the onset, middle, and termination of each episode. Descriptive characteristics (mean, SD, and RMSSD of RR intervals) were calculated within each section, and compared using a nonparametric, paired Wilcoxon test. In 25 patients (17 men, 60.6 +/- 12.2 years old), 231 episodes from 44 recordings met the selection criteria. The mean RR interval increased slightly between the onset and mid-portion of AF episodes (565.9 +/- 128.3 vs 580.3 +/- 144.7 ms, P < 0.001). The RR interval at the termination of AF was significantly greater than that at the start (627.1 +/- 156.1 vs 565.9 ms, P < 10-11) or mid-portion (627.1 +/- 156.1 vs 580.3 +/- 144.7 ms, P < 10-13). SD of the RR interval increased significantly between onset and mid-portion (111.1 +/- 60.2 vs 118.2 +/- 66.7 ms, P < 0.001) and more substantially between mid-portion and termination (118.2 +/- 66.7 vs 201.8 +/- 93.7 ms, P < 10-21). During paroxysms of AF, the mean RR interval and the variability of RR intervals increases. Termination of a paroxysm is preceded by a marked increase in RR interval variability.

Role of transcutaneous ultrasound in evaluation of graft patency following minimally invasive coronary surgery.

OBJECTIVE: Recent development in minimally invasive coronary surgery prompted us to carry out prospective evaluation of patients undergoing coronary artery bypass grafting through left anterior small thoracotomy. METHODS: Between April 1996 and February 1997, 15 patients (age 32-70, 12 male) were operated on. The left internal thoracic artery (LITA) basal flow was assessed by means of transcutaneous Duplex ultrasound scanning with pulsed waved Doppler. Eight patients were studied in the immediate postoperative period (2-4 days) and seven patients (1-7 months) following revascularisation. In addition to that, nine patients underwent coronary angiography. RESULTS: LITA graft flows were quantifiable in all 15 patients. In two patients there was a significant reduction in both time-averaged velocity and total flow. The subsequent coronary angiogram revealed severe (>50%) stenosis of LITA graft in both patients. One of these patients had a reversible obstruction documented by Duplex scanning and coronary angiography. Systolic measures did not differ between normal (13) and stenosed grafts (2), but diastolic time-averaged velocity (indicating coronary run-off) and total flow appeared lower in the latter. CONCLUSIONS: LITA flow following left anterior small thoracotomy surgery can be evaluated non-invasively. Measurement of diastolic flow (i.e. coronary perfusion rather than internal thoracic branch run-off) and total flow is useful in estimating graft function.

Mid- and long-term similarity of ventricular response to paroxysmal atrial fibrillation: digoxin versus placebo.

The effects of digoxin on ventricular response during atrial fibrillation (AF) and consequent effects on arrhythmic symptoms have still not been fully explained. This study investigated whether the treatment by digoxin contributes to mid- and long-term stabilization of ventricular cycles in patients with paroxysmal AF. A population of 45 patients with paroxysmal AF underwent 24-hour ECG recordings during each arm of a randomized crossover trial comparing digoxin and placebo. This yielded 30 Holter recordings from 22 patients that contained AF episodes lasting in excess of 2 minutes and with acceptably low Holter noise. Each AF episode was divided into nonoverlapping segments of 30 seconds and the distribution of RR intervals in each segment was compared with the distribution of all other AF segments in the same recording using the Kolmogorov-Smirnov test. The percentage of tests that revealed significant differences at levels of P < or = 0.01, and P < or = 0.001 were sorted according to the time between the segments compared. The comparisons of these results were performed between: (a) all recordings on placebo (n = 16) and all recordings on digoxin (n = 14), and (b) between recordings on placebo and on digoxin in 8 patients in whom paired analysis was possible. Adjacent AF segments (distance 0) differed significantly only in < 30% of both recordings on placebo and on digoxin. However, with increasing the distance between segments, the proportion of the significant differences between RR interval distributions increased more with placebo than with digoxin (P < 10(-300), Chi-square test). Paired data revealed larger differences between placebo and digoxin with increasing distance between segments. Thus in patients with paroxysmal AF, digoxin leads to more reproducible patterns of ventricular cycles that may be better tolerated clinically.

Distribution of fast heart rate episodes during paroxysmal atrial fibrillation.

OBJECTIVE: To investigate the defibrillator waiting time (time between the recognition of atrial fibrillation and the actual shock) by studying paroxysmal atrial fibrillation episodes with RR intervals shorter than a certain limit (that is, episodes during which defibrillation should not be attempted). METHODS: Long term 24 hour Holter recordings from a digoxin v placebo crossover study in patients with paroxysmal atrial fibrillation were analysed. In all, 23 recordings with atrial fibrillation episodes of at least 1000 ventricular cycles and with < 20% Holter artefacts or noise were used (11 recorded on placebo and 12 on digoxin). For each recording, the mean ("mean waiting time") and maximum ("maximum waiting time") duration of continuous sections of atrial fibrillation episodes with all RR intervals shorter than a certain threshold were evaluated, ranging the threshold from 400 to 1000 ms in 10 ms steps. For each threshold, the mean and maximum waiting times were compared between recordings on placebo and on digoxin. RESULTS: Both the mean and maximum waiting times increased exponentially with increasing threshold. Practically acceptable mean waiting times less than one minute were observed with thresholds below 600 ms. There were no significant differences in mean waiting times and maximum waiting times between recordings on placebo and digoxin, and only a trend towards shorter waiting times on digoxin. CONCLUSIONS: Introduction of a minimum RR interval threshold required to deliver atrial defibrillation leads to practically acceptable delays between atrial fibrillation recognition and the actual shock. These delays are not prolonged by digoxin treatment.

Analysis of the cardiac rhythm preceding episodes of paroxysmal atrial fibrillation.

AIMS: This study seeks to elucidate whether there was a common mode of initiation of paroxysmal atrial fibrillation (PAF) episodes that might suggest new therapies. METHODS: A library of 177 digitized and analyzed 24-hour Holter recordings from PAF pharmacotherapy trials was studied. All noise-free PAF episodes > or =0.5 minutes were identified. PAF episodes and the preceding 2 minutes of sinus rhythm were printed as tachograms and visually inspected. Heart rate and ectopic beat behavior were used to characterize modes of PAF onset by comparing half-minute segments of the final 2 minutes of sinus rhythm. RESULTS: Thirty-four recordings (from 19 patients, aged 61.7 +/- 11.5 years) provided 231 PAF episodes suitable for analysis. No patients had a consistent mode of PAF onset. This was confirmed by systematic analysis of the five patients with the most episodes. Overall, a highly significant increase in ectopic beats, from 1.34 to 6.52 min(-1) (p < 0.001) was found, but heart rate did not significantly change (mean heart rate at onset = 64 beats/min). PAF was initiated by a solitary ectopic beat in more than half of the cases. No consistent evidence for short-long-short sequences, seen in ventricular arrhythmias, was found. CONCLUSION: The mode of onset of atrial fibrillation is inconsistent, both across a population with PAF and within individuals. This has implications for understanding the mechanisms of atrial fibrillation onset in human beings and for the treatment of the disorder.

A relationship between fluctuations in heart rate and the duration of subsequent episodes of atrial fibrillation.

A relationship between autonomic tone and the onset of paroxysmal atrial fibrillation in some patients is recognised. Episodes of PAF may vary enormously in duration, however, from a few beats to many hours. Whether autonomic tone influences the duration of the episodes has been less well investigated. From a database of Holter recording taken from patients with symptomatic PAF, we identified all episodes of at least 30 seconds duration which were preceded by noise free sinus rhythm. This study examined the heart rate prior to AF onset, the change in heart rate over the final minute of sinus rhythm and the time of AF onset, and compared the data from those episodes of AF of more than 5 minutes duration to the shorter ones. Heart rate was slower before long episodes of AF, but this was found to predominantly represent data from separate recordings. A highly significant rise in heart rate was detected prior to long AF episodes compared to shorter ones. Daytime AF episodes were slightly longer than nocturnal ones. The most important finding was that longer AF episodes were typified by a heart rate acceleration. This suggests that, regardless of underlying aetiology, and increase in sympathetic tone may be important in the sustenance of episodes of PAF.

Graphical representation of complex data--diurnal patterns of initiations of atrial fibrillation episodes.

A construction of a purpose designed graphical display is demonstrated in a study investigating the circadian distribution of patterns of RR interval sequences preceding episodes of paroxysmal atrial fibrillation (PAF). Based on a comparison with a (80%, 120%) range around the median of preceding 10 RR intervals, each RR interval is classified as normal, short, or long. Classifications of RR intervals in n-tuplets (n = 1, ...,5) preceding PAF episodes are used to compute probabilities of individual types of sequences occurring within 4-hour periods of the day (between 1 am, 5 am, 9 am, 1 pm, 5 pm, and 9 pm). Graphical representation of the data is proposed using a hierarchy of bar graphs. The graphical system has been filled with data of 327 atrial fibrillation episodes recorded in 46 24-hour ECGs in PAF patients. The graphical analysis supports a link between PAF initiation and cardiac autonomic status.

Recurrent syncope due to complete atrioventricular block, a rare presenting symptom of otherwise silent coronary artery disease: successful treatment by PTCA.

A patient presented with recurrent syncope and episodes of AV block preceded by asymptomatic ST segment elevation on ambulatory monitoring. Coronary angiography revealed a severe stenosis in the midsegment of the right coronary artery (RCA). Successful PTCA and stent insertion abolished further episodes of syncope.

Multicenter low energy transvenous atrial defibrillation (XAD) trial results in different subsets of atrial fibrillation.

OBJECTIVES: This prospective, multicenter trial was aimed at defining efficacy and safety of low energy shocks during atrial fibrillation in a diverse cohort of patients. BACKGROUND: Experimental studies in sheep and preliminary data in humans have suggested that low energy internal shocks delivered between right atrial and coronary sinus electrode catheters may terminate atrial fibrillation. METHODS: Biphasic 3/3-ms R wave synchronous shocks were delivered between two electrode catheters in the right atrium and coronary sinus. The defibrillation protocol started with a test shock of 20 V, and shocks increased in 40-V steps until restoration of sinus rhythm or a maximum of 400 V. Shock delivery was withheld after short RR intervals. In 141 patients with atrial fibrillation, the protocol was carried out under sedation in case the shock was associated with discomfort. The atrial arrhythmia was paroxysmal (< or = 7 days) in 50 patients, chronic (> 30 days) in 53, intermediate (> 7 days, < or = 30 days) in 18 and induced in 20. Underlying heart disease was present in 88 patients (62%). RESULTS: Paroxysmal atrial fibrillation was successfully terminated in 46 (92%) of 50 patients, chronic atrial fibrillation in 37 (70%) of 53, intermediate in 16 (89%) of 18 and induced in 16 (80%) of 20. Mean conversion threshold was 1.8 J (213 V) in the induced group, 2.0 J (229 V) in the paroxysmal group, 2.8 J (272 V) in the intermediate group and 3.6 J (311 V) in the chronic group. The conversion voltage was significantly (p < 0.001) higher in the chronic group than in the other groups of atrial fibrillation and increased significantly with the duration of atrial fibrillation and with left atrial size (p < 0.05). Of 1,779 R wave synchronized shocks delivered with a mean (+/-SD) preceding RR interval of 676 +/- 149 ms, no ventricular arrhythmia was induced. The latter may occur after unsynchronized shocks. CONCLUSIONS: Low energy transvenous shocks in patients with atrial fibrillation are effective and safe, provided that shocks are properly synchronized to R waves with preceding RR intervals that meet appropriate cycle length criteria. This study provides data that may be useful in the development of an implanted atrial defibrillator.