Chromatic summation and receptive field properties of blue-on and blue-off cells in marmoset lateral geniculate nucleus.

The "blue-on" and "blue-off" receptive fields in retina and dorsal lateral geniculate nucleus (LGN) of diurnal primates combine signals from short-wavelength sensitive (S) cone photoreceptors with signals from medium/long wavelength sensitive (ML) photoreceptors. Three questions about this combination remain unresolved. Firstly, is the combination of S and ML signals in these cells linear or non-linear? Secondly, how does the timing of S and ML inputs to these cells influence their responses? Thirdly, is there spatial antagonism within S and ML subunits of the receptive field of these cells? We measured contrast sensitivity and spatial frequency tuning for four types of drifting sine gratings: S cone isolating, ML cone isolating, achromatic (S + ML), and counterphase chromatic (S - ML), in extracellular recordings from LGN of marmoset monkeys. We found that responses to stimuli which modulate both S and ML cones are well predicted by a linear sum of S and ML signals, followed by a saturating contrast-response relation. Differences in sensitivity and timing (i.e. vector combination) between S and ML inputs are needed to explain the amplitude and phase of responses to achromatic (S + ML) and counterphase chromatic (S - ML) stimuli. Best-fit spatial receptive fields for S and/or ML subunits in most cells (>80%) required antagonistic surrounds, usually in the S subunit. The surrounds were however generally weak and had little influence on spatial tuning. The sensitivity and size of S and ML subunits were correlated on a cell-by-cell basis, adding to evidence that blue-on and blue-off receptive fields are specialised to signal chromatic but not spatial contrast.

Temporal response properties of koniocellular (blue-on and blue-off) cells in marmoset lateral geniculate nucleus.

Visual perception requires integrating signals arriving at different times from parallel visual streams. For example, signals carried on the phasic-magnocellular (MC) pathway reach the cerebral cortex pathways some tens of milliseconds before signals traveling on the tonic-parvocellular (PC) pathway. Visual latencies of cells in the koniocellular (KC) pathway have not been specifically studied in simian primates. Here we compared MC and PC cells to "blue-on" (BON) and "blue-off" (BOF) KC cells; these cells carry visual signals originating in short-wavelength-sensitive (S) cones. We made extracellular recordings in the lateral geniculate nucleus (LGN) of anesthetized marmosets. We found that BON visual latencies are 10-20 ms longer than those of PC or MC cells. A small number of recorded BOF cells (n = 7) had latencies 10-20 ms longer than those of BON cells. Within all cell groups, latencies of foveal receptive fields (<10° eccentricity) were longer (by 3-8 ms) than latencies of peripheral receptive fields (>10°). Latencies of yellow-off inputs to BON cells lagged the blue-on inputs by up to 30 ms, but no differences in visual latency were seen on comparing marmosets expressing dichromatic ("red-green color-blind") or trichromatic color vision phenotype. We conclude that S-cone signals leaving the LGN on KC pathways are delayed with respect to signals traveling on PC and MC pathways. Cortical circuits serving color vision must therefore integrate across delays in (red-green) chromatic signals carried by PC cells and (blue-yellow) signals carried by KC cells.

Modulation of gamma oscillations by endogenous adenosine through A1 and A2A receptors in the mouse hippocampus.

Adenosine serves as a homeostatic factor, regulating hippocampal activity through A(1) receptor-mediated inhibition. Gamma frequency oscillations, associated with cognitive functions, emerge from increased network activity. Here we test the hypothesis that hippocampal gamma oscillations are modulated by ambient adenosine levels. In mouse hippocampal slices exogenous adenosine suppressed the power of both kainate-induced gamma oscillations and spontaneous gamma oscillations, observed in a subset of slices in normal aCSF. Kainate-induced gamma oscillation power was suppressed by the A(1) receptor agonist PIA and potentiated by the A(1) receptor antagonist 8-CPT to three times matched control values with an EC(50) of 1.1microM. 8-CPT also potentiated spontaneous gamma oscillation power to five times control values. The A(2A) receptor agonist CGS21680 potentiated kainate-induced gamma power to two times control values (EC(50) 0.3nM), but this effect was halved in the presence of 8-CPT. The A(2A) receptor antagonist ZM241385 suppressed kainate-induced gamma power. The non-selective adenosine receptor antagonist caffeine induced gamma oscillations in slices in control aCSF and potentiated both kainate-induced gamma and spontaneous gamma oscillations to three times control values (EC(50) 28muM). Decreasing endogenous adenosine levels with adenosine deaminase increased gamma oscillations. Increasing endogenous adenosine levels with the adenosine kinase inhibitor 5-iodotubericidin suppressed gamma oscillations. Partial hypoxia-induced suppression of gamma oscillations could be prevented by 8-CPT. These observations indicate that gamma oscillation strength is powerfully modulated by ambient levels of adenosine through A(1) receptors, opposed by A(2A) receptors. Increased gamma oscillation strength is likely to contribute to the beneficial cognitive effects of caffeine.

Quality assessment of pacemaker implantations in Denmark.

AIMS: Quality assessment of therapeutic procedures is essential to insure a cost-effective health care system. Pacemaker implantation is a common procedure with more than 500,000 implantations world-wide per year, but the general complication rate is not well described. We studied procedure related complications for all implantations performed in an entire nation over a 3-year period. METHODS AND RESULTS: A prospective study of complications related to 99% of the 5648 primary pacemaker implantations performed in the 12 Danish pacemaker centres in 1997-1999 was carried out. Overall 76% of the patients received a physiological pacemaker system and 91% received the optimal pacing mode according to international guidelines. Perioperative complications requiring reoperation were: haematoma 0.3%, atrial lead related 1.9%, ventricular lead related 1.7%. Late complications requiring reoperation were: infection 02%, atrial lead related 13%, ventricular lead related 1.2%. The complication rate decreased over the study period, but overall the complication rate was higher than expected and showed considerable variation between centres. CONCLUSIONS: Our results demonstrate that sensitive data such as complications related to pacemaker implantations can be collected on a national basis. We suggest that a reoperation rate higher than 3% for atrial as well as ventricular pacing electrodes in the individual implanting centre should cause the centre to evaluate carefully the procedure as well as the performance of the individual implanter.

Prolonged QTc interval predicts mortality in patients with Type 1 diabetes mellitus.

AIMS: To evaluate prolonged QTc interval and QT dispersion as predictors of all-cause and cardiovascular mortality after adjustment for well-established risk factors in Type 1 diabetic patients. METHODS: From a cohort of all adult Type 1 diabetic patients, duration of diabetes >or= 5 years, attending the clinic in 1984 and followed in an observational study for 10 years (n = 939), all subjects with resting baseline electrocardiograms were identified (n = 697, 360 males). The QT length was measured and corrected for heart rate (QTc). Maximal QTc length (QTc max) and QT dispersion were determined. RESULTS: At baseline, 431 had normoalbuminuria (< 30 mg/24 h), 138 had microalbuminuria (30-299 mg/24 h) and 128 had macroalbuminuria (>or= 300 mg/24 h) of whom 66 (15%), 35 (25%) and 61 (48%) died during follow-up, respectively (26 (6%), 14 (10%), 21 (16%) from cardiovascular disease). QTc max. was 442 (1.2) ms (mean (SEM)) for survivors and 457 (3.7) in patients who died (P < 0.001). In a Cox proportional hazards model including baseline values of putative risk factors, independent predictors of death were QTc max (P = 0.03), age (P < 0.001), presence of hypertension (P = 0.001), male sex (P < 0.001), log urinary albumin excretion (P < 0.001), smoking (P = 0.04), log serum-creatinine (P < 0.001), height (P < 0.001), low social class (P = 0.04), whereas QT dispersion, heart rate, and HbA1c were not included. In the subgroup with macroalbuminuria, but not for all patients, QTc max was an independent risk factor for cardiovascular mortality. CONCLUSION: QTc prolongation, but not increased QT dispersion, is an independent marker of increased mortality in patients with Type 1 diabetes mellitus.

QTc interval length and QT dispersion as predictors of mortality in patients with non-insulin-dependent diabetes.

Patients with non-insulin-dependent diabetes (NIDDM) are at independent risk of cardiovascular death. The reason is only partially understood. The aim of our study was therefore to evaluate the impact of corrected QT interval length (QTc) and QT dispersion (QT-disp) on mortality in a cohort of 324 Caucasian NIDDM patients. A resting 12-lead ECG was recorded at baseline. Maximum (QT-max) and minimum QT (QT-min) intervals were measured, and QT-max was corrected for heart rate (QTc-max). QT-disp was defined as the difference between QT-max and QT-min. QTc-max was 454 (376-671) ms(1/2) (median (range)) and QT-disp 61 (0-240) ms. Prolonged QTc interval (PQTc), defined as QTc-max > 440 ms(1/2), was present in 67% of the patients and prolonged QT-disp (PQT-disp), defined as QT-disp > 50 ms, was present in 51%. During the 9-year follow-up period, 100 patients died (52 from cardiovascular diseases). Thirty-seven percent of the patients with PQTc died compared with 17% with normal QTc interval (p<0.001). The Cox proportional hazard model, including putative risk factors at baseline, revealed the following independent predictors of all cause mortality; QTc-max (p<0.05), age (p<0.0001), albuminuria (p<0.01), retinopathy (p<0.01), HbA1c (p<0.05), insulin treatment (p<0.01), total cholesterol (p<0.01), serum creatinine (p<0.05) and presence of cardiac heart disease based on Minnesota coded ECG (p<0.001). Whereas QT-disp was not a predictor, QTc-max interval was an independent predictor of cardiovascular mortality. Our study showed a high prevalence of QTc and QT-disp abnormalities and indicated that QTc-max but not QT-disp is an independent predictor of all cause and cardiovascular mortality in NIDDM patients.

Apoptin.

Tumor cells are often characterized by the traithey are more resistant to apoptosis induced by e.g. cytotoxic agents than normal cells. Resistance to apoptosis induction can be a direct consequence of mutations in certain tumor-suppressor genes (p53) or of certain proto-oncogenes (Bcl-2). Therefore, new cancer therapies are under development to bypass the resistance to chemo- and radio-therapy of tumors. Apoptin acts independently of p53, is stimulated by Bcl-2 and is insensitive to BCR-ABL, which means that Apoptin can induce apoptosis in cases where present (chemo)-therapeutic agents, unfortunately, will fail. The fact that Apoptin induces apoptosis in human tumorigenic cells but not in normal diploid cells, implies that side-effects of Apoptin treatment are expected to be minor. In-vivo results with a first prototype of anti-tumor therapy based on expression of Apoptin indicate that Apoptin has low acute toxicity and is effective as an anti-tumor agent.

Tissue temperatures and lesion size during irrigated tip catheter radiofrequency ablation: an in vitro comparison of temperature-controlled irrigated tip ablation, power-controlled irrigated tip ablation, and standard temperature-controlled ablation.

The limited success rate of radiofrequency catheter ablation in patients with ventricular tachycardias related to structural heart disease may be increased by enlarging the lesion size. Irrigated tip catheter ablation is a new method for enlarging the size of the lesion. It was introduced in the power-controlled mode with high power and high infusion rate, and is associated with an increased risk of crater formation, which is related to high tissue temperatures. The present study explored the tissue temperatures during temperature-controlled irrigated tip ablation, comparing it with standard temperature-controlled ablation and power-controlled irrigated tip ablation. In vitro strips of porcine left ventricular myocardium were ablated. Temperature-controlled irrigated tip ablation at target temperatures 60 degrees C, 70 degrees C, and 80 degrees C with infusion of 1 mL saline/min were compared with standard temperature-controlled ablation at 70 degrees C and power-controlled irrigated tip ablation at 40 W, and infusion of 20 mL/min. Lesion size and tissue temperatures were significantly higher during all modes of irrigated tip ablation compared with standard temperature-controlled ablation (P < 0.05). Lesion volume correlated positively with tissue temperature (r = 0.87). The maximum recorded tissue temperature was always 1 mm from the ablation electrode and was 67 +/- 4 degrees C for standard ablation and 93 +/- 6 degrees C, 99 +/- 6 degrees C, and 115 +/- 13 degrees C for temperature-controlled irrigated tip ablation at 60 degrees C, 70 degrees C, and 80 degrees C, respectively, and 112 +/- 12 degrees C for power-controlled irrigated tip ablation, which for irrigated tip ablation was significantly higher than tip temperature (P < 0.0001). Crater formation only occurred at tissue temperatures > 100 degrees C. We conclude that irrigated tip catheter ablation increases lesion size and tissue temperatures compared with standard ablation in the temperature-controlled mode at the same or higher target temperatures and in the power-controlled mode. Furthermore, tissue temperature and delivered power are the best indicators of lesion volume during temperature-controlled ablation.

Specific tumor-cell killing with adenovirus vectors containing the apoptin gene.

Specificity is an essential prerequisite for cancer gene therapy. Recently we described that apoptin, a protein of 121 amino acids which is derived from the chicken anemia virus, induces programmed cell death or apoptosis in transformed and malignant cells, but not in normal, diploid cells (Danen-van Oorschot AAAM et al, Proc Natl Acad Sci USA 1997; 94: 5843-5847). This protein has an intrinsic specificity that allows it to selectively kill tumor cells, irrespective of the p53 or Bcl-2 status of these cells. Hence, it is attractive to explore the use of the apoptin gene for therapeutic applications, viz cancer gene therapy. In this paper, we describe the generation and characterization of an adenovirus vector, AdMLPvp3, for the expression of apoptin. Despite the fact that apoptin ultimately induces apoptosis in the helper cells, which are transformed by the adenovirus type 5 early region 1 (E1), the propagation kinetics and yields of AdMLPvp3 are similar to those of control vectors. Infection with AdMLPvp3 of normal rat hepatocytes in cell culture did not increase the frequency of apoptosis. In contrast, in the hepatoma cell lines HepG2 and Hep3b, infection with AdMLPvp3, but not with control vectors, led to a rapid induction of programmed cell death. Experiments in rats demonstrated that AdMLPvp3 could be safely administered by intraperitoneal, subcutaneous or intravenous injection. Repeated intravenous doses of AdMLPvp3 were also well tolerated, indicating that the apoptin-expressing virus can be administered without severe adverse effects. In a preliminary experiment, a single intratumoral injection of AdMLPvp3 into a xenogeneic tumor (HepG2 cells in Balb/Cnu/nu mice) resulted in a significant reduction of tumor growth. Taken together, our data demonstrate that adenovirus vectors for the expression of the apoptin gene may constitute a powerful tool for the treatment of solid tumors.

Temperature-controlled radiofrequency ablation of cardiac tissue: an in vitro study of the impact of electrode orientation, electrode tissue contact pressure and external convective cooling.

BACKGROUND: A variety of basic factors such as electrode tip pressure, flow around the electrode and electrode orientation influence lesion size during radiofrequency ablation, but importantly is dependent on the chosen mode of ablation. However, only little information is available for the frequently used temperature-controlled mode. The purpose of the present experimental study was to evaluate the impact during temperature-controlled radiofrequency ablation of three basic factors regarding electrode-tissue contact and convective cooling on lesion size. METHODS AND RESULTS: In vitro strips of porcine left ventricular myocardium were ablated in a tissue bath. Temperature-controlled ablation at 80 degrees C for 60 s was performed using a 7F 4 mm tip electrode in either perpendicular or parallel contact with the endocardium at a pressure of 10 or 20 g. Increased flow around the electrode was induced by circulating the saline in the tissue bath at a flow-velocity of 0.1 m/s. Lesion volume was determined by cutting lesions in 1 mm thick slices, staining with nitroblue tetrazolium and planimetering. A total of 107 lesions was created. Lesion size was significantly larger for perpendicular electrode orientation compared to parallel for both pressure-settings and both levels of flow around the electrode (p < 0.05). Increased flow around the electrode enlarged lesion size (p < 0.005). Electrode-tissue contact pressure had no significant impact on lesion size. CONCLUSIONS: During temperature-controlled radiofrequency ablation increased external cooling of the electrode tip due to either flow of the surrounding liquid or poor electrode tissue contact, as exemplified by perpendicular versus parallel electrode orientation, increases lesion size significantly. This is in contrast to the impact of these factors during power-controlled ablation due to the lack of increased power-delivery in the latter situation.

Lesion dimensions during temperature-controlled radiofrequency catheter ablation of left ventricular porcine myocardium: impact of ablation site, electrode size, and convective cooling.

BACKGROUND: It is important to increase lesion size to improve the success rate for radiofrequency ablation of ischemic ventricular tachycardia. This study of radiofrequency ablation, with adjustment of power to approach a preset target temperature, ie, temperature-controlled ablation, explores the effect of catheter-tip length, ablation site, and convective cooling on lesion dimensions. METHODS AND RESULTS: In vitro strips of porcine left ventricular myocardium during different levels of convective cooling and in vivo pig hearts at 2 or 3 left ventricular sites were ablated with 2- to 12-mm-tip catheters. We found increased lesion volume for increased catheter-tip length

[Treatment of hypertrophic cardiomyopathy]. / Behandling af hypertrofisk kardiomyopati.

The medical management of hypertrophic cardiomyopathy is reviewed. Four cases of hypertrophic cardiomyopathy are presented, and serve to describe the currently available invasive treatment modalities, i.e. septal myectomy, dual chamber pacing, cardioverter defibrillator implantation and heart transplantation. These different invasive treatments all seem to be symptomatically effective in carefully selected patients, but studies of prognostic effects are not available. Finally, new experimental procedures are presented.

Detection of K-ras point mutations in sputum from patients with adenocarcinoma of the lung by point-EXACCT.

PURPOSE: Kirsten ras (K-ras) point mutations are found in 30% to 56% of pulmonary adenocarcinomas by means of highly sensitive techniques. Recently, the Point-EXACCT (point mutation detection using exonuclease amplification coupled capture technique) method was described, which detected one cell with a mutation in 15,000 normal cells. The aim of this study was to examine whether K-ras point mutations could be found with this rapid method in the sputum of patients with adenocarcinoma of the lung. PATIENTS AND METHODS: DNA from paraffin-embedded adenocarcinoma and corresponding sputum samples were analyzed for mutations of the K-ras gene. Twenty-eight biopsy specimens and 54 sputum samples of 22 patients were used for amplification and K-ras codon 12 point mutation detection. RESULTS: In 11 of 22 patients (50%), a mutation in K-ras codon 12 was shown in the tumor sample. In five of 11 patients (45%) with a K-ras mutation in the tumor, the same type of mutation was identified in at least one sputum sample. A mutation could not be detected in any of the sputum samples from patients with a K-ras-negative tumor. Time between K-ras point mutation detection in sputum and clinical diagnosis of lung cancer varied from 1 month to almost 4 years. In two of the five patients with K-ras-positive sputum specimens, malignant cells were found with cytologic examination. CONCLUSION: Point-EXACCT is suitable for the detection of K-ras point mutations in sputum samples of patients with adenocarcinoma of the lung. This approach may be an important adjunct to cytology in the early diagnosis of lung cancer.

Temperature-controlled irrigated tip radiofrequency catheter ablation: comparison of in vivo and in vitro lesion dimensions for standard catheter and irrigated tip catheter with minimal infusion rate.

INTRODUCTION: In patients with ventricular tachycardias due to structural heart disease, catheter ablation cures < 60% partly due to the limited lesion size after conventional radiofrequency ablation. Irrigated tip radiofrequency ablation using power control and high infusion rates enlarges lesion size, but has increased risk of cratering. The present study explores irrigated tip catheter ablation in temperature-controlled mode, target temperature 60 degrees C, using an irrigation rate of 1 mL/min, comparing this to conventional catheter technique, target temperature 80 degrees C. METHODS AND RESULTS: In vivo anesthetized pigs were ablated in the left ventricle. In vitro strips of porcine left ventricular myocardium were ablated in a tissue bath. Lesion volume was significantly larger after irrigated tip ablation both in vivo (544 +/- 218 vs 325 +/- 194 mm3, P < 0.01) and in vitro (286 +/- 113 vs 179 +/- 23 mm3, P < 0.001). The incidence of cratering was not significantly different between the two groups. In vivo, no coagulum formation on part of the catheter tip was seen after irrigated tip ablation as opposed to 52% of the applications with conventional ablation (P < 0.05). CONCLUSION: We conclude that temperature-controlled radiofrequency ablation with irrigated tip catheters using low target temperature and low infusion rate enlarges lesion size without increasing the incidence of cratering and reduces coagulum formation of the tip.

Implantation of active can implantable defibrillators in the right pectoral region.

Routinely the active can ICD is placed in the left side pectoral position, which theoretically gives optimal conditions for a low defibrillation threshold. Some patients, however, demand a right pectoral position, which possibly could result in a higher defibrillation threshold. A right pectoral position was used in 3 of 85 active can ICDs implanted in our institution from 1994. The DFT was 12 J in two and 18 J in one patient. Thus, right pectoral implantation is feasible and offers an alternative approach in selected patients.

Lesion size in relation to ablation site during radiofrequency ablation.

This study was designed to investigate the effect of the convective cooling of the tip of the ablation electrode during temperature controlled radiofrequency ablation. In vivo two different application sites in the left ventricle of anaesthetised pigs were ablated and in vitro ablation was performed during two different flow-velocities in a tissue bath, while electrode contact pressure and position were unchanged. Target temperature was 80 degrees C. Obtained tip temperature, power consumption and lesion dimensions were measured. In vivo lesion volume, depth and width were found significantly larger for septal applications than apical applications (p < 0.01) and more power was used (p < 0.001). Obtained tip temperature was significantly lower in the septal applications (p < 0.001). In vitro increased convective cooling by induction of flow yielded larger lesion volume, depth and width (p < 0.01), and had higher power consumptions (p < 0.01). Obtained tip temperature did not differ significantly. For the given chosen target temperature power consumption was positively related to lesion volume (r = 0.66 in vivo and 0.65 in vitro), whereas obtained tip temperature was not (r = -0.49 in vivo and -0.61 in vitro). We conclude that during temperature controlled radiofrequency ablation lesion size differs for septal and apical left ventricular applications. Differences in convective cooling might play an important role in this respect. This is supported by our in vitro experiments, where increased convective cooling by induction of a flow around the electrode tip increases lesion dimensions and power consumptions. Furthermore we conclude that for the given target temperature the power consumption is positively correlated with lesion volume (p < 0.001), whereas the obtained tip temperature is not.

Comparison of threshold values between steroid and nonsteroid unipolar membrane leads.

The aim of this study was to evaluate whether steroid membrane leads can reduce pacing thresholds and thereby save energy as compared to nonsteroid membrane leads. The study was a random sample, double blind test consisting of 90 patients between 49-94 years of age admitted to seven hospitals in Europe for pacemaker implantation. The two leads compared in this study had contoured activated carbon tips covered with ion exchange membranes. The leads were identical except that 30 micrograms of dexamethasone was dissolved in the ion exchange membrane of one of the leads. Normal lead implant procedures were used. Follow-up procedures were conducted at 2 weeks and 1, 3, 6, and 12 months after lead implantation. The pulse generator was programmed to an amplitude of 2.5 or 5 V and a duration of 0.5 msec. The stimulation threshold was measured using the VARIO function. The threshold was measured a total of three times in order to determine the presence of microdislocations. At the 2- and 4-week follow-ups, the stimulation threshold was significantly lower for the steroid leads than for the membrane leads without steroid (0.54 +/- 0.19 vs 0.76 +/- 0.25 V, P = 0.0005; and 0.59 +/- 0.19 vs 0.74 +/- 0.26 V, P = 0.005), but after 3 months, the threshold values were almost the same for both leads.

[Diagnosis of long QT syndrome with the help of atropine provoked ventricular tachycardia]. / Diagnostik af langt QT-syndrom med ventrikulaer takykardi ved hjaelp af atropininjektion.

A 49-year-old woman was admitted because of several syncopes during sports activity. She was appeared well, and the physical examination revealed no pathological findings, particularly no heart murmurs. The electrocardiogram had a normal PQ, QRS and the corrected QT (QTc)interval was 0.44 s. During the exercise test no arrhythmias were seen and the QTc was unchanged of 0.44 s, but 0.6 mg atropine injected intravenously provoked prolonged QTc = 0.49 s followed by nonsustained ventricular tachycardia. Electrophysiological examination and coronary arteriography showed no inducible arrhythmias and no presence of coronary artery disease. Beta-blocker treatment was started. During one year of observation she presented no syncope, and was still active in sports. It is concluded that patients presenting with syncope and an ECG with borderline QT prolongation should undergo several provocation trials, if simple stress test is initially negative, because undiagnosed patients without prophylactic treatment have a high mortality.

Atrial fibrillation in the Wolff-Parkinson-White syndrome.

Atrial fibrillation in patients with Wolff-Parkinson-White (WPW) syndrome may lead to syncope, ventricular fibrillation, and sudden death. In a follow-up study of 241 patients with WPW syndrome in a relatively unselected population, 26 patients had documented atrial fibrillation (11%). These patients were followed up after 1-37 years (median 11 years; mean 15 years). During this period, 2 of 26 died suddenly. These 2 patients had the shortest RR interval during spontaneous atrial fibrillation (less than or equal to 220 msec), greater than or equal to 1 episodes of syncope, and a persistent delta wave in all available electrocardiograms. In comparison, sudden or tachycardia-related death was seen in 4 of the 241 patients. This difference is not statistically significant. Thus, atrial fibrillation of 26 patients with WPW syndrome was surprisingly well tolerated in our follow-up study with only 2 sudden deaths.

Serial pulmonary function tests in patients treated with low-dose amiodarone.

Problems with pulmonary toxicity have emerged as a potentially limiting factor for amiodarone use. We studied 24 consecutive patients receiving low-dose (i.e., less than or equal to 400 mg/day) amiodarone for refractory tachyarrhythmias. Serial pulmonary function test results were correlated with daily dose, serum concentration, cumulated dose, and duration of amiodarone treatment to determine the effect of the drug on pulmonary function. The mean follow-up period for the 24 patients, who completed baseline and follow-up evaluations, was 47 months (range 31 to 75 months). In 22 of the 24 patients a reduction in total diffusion capacity (TLCO) was noted after treatment; for all 24 patients the mean reduction in TLCO was 12.9% of the predicted value (SD 9.6% predicted) (p less than 0.02). The decrease in TLCO was found to be significantly related to an increasing cumulated dose of amiodarone (p = 0.007), whereas the reduction in TLCO was found to be unrelated to sex, age, underlying heart disease, arrhythmia, daily dose of amiodarone, duration of treatment, plasma concentration of amiodarone and desethylamiodarone, and pretreatment pulmonary function abnormalities. Seven (29%) of the patients had asymptomatic pulmonary toxicity with a decrease in TLCO greater than or equal to 20% of the predicted value. In conclusion, long-term treatment with low-dose amiodarone was associated with a substantial decrease in TLCO, a higher cumulative dose of the drug was related to an increasing reduction in TLCO, and pretreatment pulmonary function abnormalities were not predictive for development of subclinical pulmonary toxicity.