A trans-specific polymorphism in ZC3HAV1 is maintained by long-standing balancing selection and may confer susceptibility to multiple sclerosis.

The human ZC3HAV1 gene encodes an antiviral protein. The longest splicing isoform of ZC3HAV1 contains a C-terminal PARP-like domain, which has evolved under positive selection in primates. We analyzed the evolutionary history of this same domain in humans and in Pan troglodytes. We identified two variants that segregate in both humans and chimpanzees; one of them (rs3735007) does not occur at a hypermutable site and accounts for a nonsynonymous substitution (Thr851Ile). The probability that the two trans-specific polymorphisms have occurred independently in the two lineages was estimated to be low (P = 0.0054), suggesting that at least one of them has arisen before speciation and has been maintained by selection. Population genetic analyses in humans indicated that the region surrounding the shared variants displays strong evidences of long-standing balancing selection. Selection signatures were also observed in a chimpanzee population sample. Inspection of 1000 Genomes data confirmed these findings but indicated that search for selection signatures using low-coverage whole-genome data may need masking of repetitive sequences. A case-control study of more than 1,000 individuals from mainland Italy indicated that the Thr851Ile SNP is significantly associated with susceptibility to multiple sclerosis (MS) (odds ratio [OR] = 1.47, 95% confidence intervals [CI]: 1.08-1.99, P = 0.011). This finding was confirmed in a larger sample of 4,416 Sardinians cases/controls (OR = 1.18, 95% CI: 1.037-1.344, P = 0.011), but not in a population from Belgium. We provide one of the first instances of human/chimpanzee trans-specific coding variant located outside the major histocompatibility complex region. The selective pressure is likely to be virus driven; in modern populations, this variant associates with susceptibility to MS, possibly via the interaction with environmental factors.

Variation within the CLEC16A gene shows consistent disease association with both multiple sclerosis and type 1 diabetes in Sardinia.

Variation within intron 19 of the CLEC16A (KIAA0350) gene region was recently found to be unequivocally associated with type 1 diabetes (T1D) in genome-wide association (GWA) studies in Northern European populations. A variant in intron 22 that is nearly independent of the intron 19 variant showed suggestive evidence of association with multiple sclerosis (MS). Here, we genotyped the rs725613 polymorphism, representative of the earlier reported associations with T1D within CLEC16A, in 1037 T1D cases, 1498 MS cases and 1706 matched controls, all from the founder, autoimmunity-prone Sardinian population. In these Sardinian samples, allele A of rs725613 is positively associated not only with T1D (odds ratio=1.15, P one-tail=5.1 x 10(-3)) but also, and with a comparable effect size, with MS (odds ratio=1.21, P one-tail 6.7 x 10(-5)). Taken together these data provide evidence of joint disease association in T1D and MS within CLEC16A and underline a shared disease pathway.

Management of syncope referred urgently to general hospitals with and without syncope units.

OBJECTIVE: We tested the hypothesis that management of patients with syncope admitted urgently to a general hospital may be influenced by the presence of an in-hospital structured syncope unit. BACKGROUND: The management of syncope is not standardized. Methods We compared six hospitals equipped with a syncope unit organized inside the department of cardiology with six matched hospitals without such facilities. The study enroled all consecutive patients referred to the emergency room from 5 November 2001 to 7 December 2001 who were affected by transient loss of consciousness as their principal symptom. RESULTS: There were 279 patients in the syncope unit hospitals and 274 in the control hospitals. In the study group, 30 (11%) patients were referred to the syncope unit for evaluation. In the study group, 12% fewer patients were hospitalized (43 vs 49%, not significant) and 8% fewer tests were performed (3.3+/-2.2 vs 3.6+/-2.2 per patient, not significant). In particular, the study group patients underwent fewer basic laboratory tests (75 vs 86%, P=0.002), fewer brain-imaging examinations (17 vs 24%, P=0.05), fewer echocardiograms (11 vs 16%, P=0.04), more carotid sinus massage (13 vs 8%, P=0.03) and more tilt testing (8 vs 1%, P=0.000). In the study group, there was a +56% rate of final diagnosis of neurally mediated syncope (56 vs 36%, P=0.000). CONCLUSION: Although only a minority of patients admitted as an emergency are referred to the syncope unit, overall management is substantially affected. It is speculated that the use of a standardized approach, such as that typically adopted in the syncope unit, is able to influence overall practice in the hospital.

Oral beclometasone dipropionate in the treatment of extensive and left-sided active ulcerative colitis: a multicentre randomised study.

AIM: To explore the efficacy and safety of the topically acting steroid beclometasone dipropionate (BDP) in an oral controlled release formulation in the treatment of extensive or left-sided ulcerative colitis. METHODS: In a multicentre, randomised, parallel-group, single-blind study, patients with active mild to moderate ulcerative colitis were randomised to a 4-week treatment with BDP 5 mg/day o.d. vs. 5-ASA 0.8 g t.d.s. The primary efficacy variable was the decrease of Disease Activity Index (DAI) (clinical symptoms and endoscopic appearance of mucosa). Safety was evaluated by monitoring adverse events, vital signs, haematochemical parameters and adrenal function. RESULTS: One hundred and seventy-seven patients were enrolled and randomly treated with BDP (n = 90) or 5-ASA (n = 87). Mean DAI score decreased in both treatments groups (P < 0.0001 vs. baseline for both groups). Clinical remission was achieved in 63.0% of patients in the BDP group vs. 62.5% in the 5-ASA group. A significant DAI score improvement (P < 0.05) in favour of BDP was observed in patients with extensive disease. Both treatments were well tolerated. Mean plasma cortisol levels were significantly reduced vs. baseline in BDP recipients, but without signs of pituitary-adrenal function depletion. CONCLUSION: Oral BDP gave an overall treatment result in patients with active ulcerative colitis without signs of systemic side-effects.

Whole-body bioelectrical impedance analysis in patients with chronic heart failure: reproducibility of the method and effects of body side.

BACKGROUND: Fluid imbalance and malnutrition have an important role in the clinical setting of chronic heart failure (CHF). Recently, tetrapolar bioelectrical impedance analysis has been suggested as an attractive method which may be used in the clinical assessment of the body composition. The aim of this study was to determine the effects of body side on whole bioelectrical impedance analysis parameters and test-retest reliability, prior to its use in a large cohort of patients. METHODS: In 114 consecutive patients with CHF (mean age 65 +/- 10 years, left ventricular ejection fraction 31 +/- 9%, NYHA functional class 2.6 +/- 0.9) we measured the total body resistance, the reactance and the derived angle phase using a single-frequency (50 KHz) tetrapolar plethysmograph device. The evaluations were performed on the left and right sides of the body, in a random order, on two different occasions 30 min apart. The effects of body side were analyzed by the Student's t-test and the test-retest reliability was computed by using the coefficient of variation and intraclass correlation coefficient. RESULTS: In both evaluations, the mean resistance value of the right side was significantly lower (almost 10 ohms) than that of the left side, the reactance was not different, and as a consequence the angle phase was significantly higher (almost 0.1 degrees) in the right than in the left side. The test-retest reliability for all the measurements considered was very high (the intraclass correlation coefficient ranged from 0.95 to 0.99 and the coefficient of variation from 1.7 to 4.3%). CONCLUSIONS: In CHF, the body side is important for the whole-body assessment of the resistance and the angle phase, but not for reactance. In addition, all these measurements are characterized by an excellent test-retest reliability and, consequently, do not necessitate a substantial increase in the sample size for the detection of small differences in experimental studies.

[Cardiopulmonary sensitivity and chemosensitivity]. / Sensibilità cardiopolmonare e chemosensibilità.

The autonomic control of the cardiovascular system plays an important role in maintaining the arterial pressure at the levels necessary for adequate tissue perfusion. In cardiovascular diseases, the impairment of the basic reflex mechanisms that are responsible for the moment-to-moment regulation could increase sympathetic activity and is correlated with an adverse outcome. The objective of the present review was to provide information about the methodological aspects exploring cardiopulmonary and chemoreceptor reflexes. Different techniques are available and all of them include assessment of reflexes through the activation or deactivation of either the cardiopulmonary baroreceptors or chemoreceptors. Intravenous saline load, head-down tilt, passive legs raising, head-out water immersion and the application of a lower body positive pressure are the principal methods utilized for activating cardiopulmonary baroreceptors; on the contrary deactivation could be achieved by acutely induced hypovolemia by furosemide or blood donation, inflation of a congestion cuff on the thighs or application of a negative pressure on the lower body. The transient exposure to a hypoxic or a hypercapnic gas mixture is frequently used to determine the peripheral and central chemoreflexes, respectively. The reflexes are quantified by the gain between output (i.e. heart rate, sympathetic activity, vascular resistance, ventilation) and input (oxygen saturation, end-tidal CO2 or changes in central venous pressure). One important limitation in assessing the cardiopulmonary baroreflex by using currently available techniques is that the involvement of the arterial baroreflex cannot be avoided. In addition, chemoreflexes cannot be interpreted unless the breathing rate is controlled. To date, several techniques are available for the quantification of cardiopulmonary baroreceptor and chemoreceptor reflexes and could provide new information on the abnormal autonomic mechanisms contributing to the pathophysiology of several cardiovascular diseases.

Depression but not anxiety influences the autonomic control of heart rate after myocardial infarction.

AIMS: It has been previously hypothesized that the adverse outcome observed in depressed patients after myocardial infarction might be due to an imbalance in autonomic nervous system activity. The aim of this study was to define the role of depressive and anxious symptoms in influencing autonomic control of heart rate after myocardial infarction. METHODS AND RESULTS: The SD of RR intervals, baroreflex sensitivity, and depression and anxiety (Zung's scales) were assessed before discharge in 103 patients with acute myocardial infarction; 32 were found to be depressed. Among the patients who were not taking beta-blockers, those with depression had significantly lower SDs of RR intervals and baroreflex sensitivity than did those without depression (96.3 +/- 22.2 ms vs 119.5 +/- 37.7 ms, P =.016; 8.6 +/- 6.2 ms vs 11.8 +/- 6.5 ms/mm Hg, P =.01, respectively). No differences were found when anxiety was considered or when beta-blockers were given. Among the patients not taking beta-blockers, there was a significant correlation between depression levels and both the SD of RR intervals (r = -0.47) and baroreflex sensitivity (r = -0.40). CONCLUSIONS: In patients with myocardial infarction, depression but not anxiety negatively influences autonomic control of heart rate. Beta-blockers modify these influences.

Ticlopidine versus aspirin after myocardial infarction (STAMI) trial.

OBJECTIVES: We sought to compare the efficacy of aspirin and ticlopidine in survivors of acute myocardial infarction (AMI) treated with thrombolysis. BACKGROUND: The role of ticlopidine in secondary prevention after AMI has not yet been explored. METHODS: Of 4,696 patients with AMI treated with thrombolysis who were screened, 261 died in the hospital (5.6%) and 1,470 were enrolled in this randomized, double-blind, multicenter trial and allocated to treatment with either aspirin (160 mg/day) or ticlopidine (500 mg/day). The most frequent reasons for exclusion were refusal to give informed consent, planned myocardial revascularization, risk of noncompliance with study procedures, need for anticoagulant therapy and contraindications to the study treatments. The primary end point was the first occurrence of any of the following events during the six-month follow-up: fatal and nonfatal AMI, fatal and nonfatal stroke, angina with objective evidence of myocardial ischemia, vascular death or death due to any other cause. RESULTS: The primary end point was recorded in 59 (8.0%) of the 736 aspirin-treated and 59 (8.0%) of the 734 ticlopidine-treated patients (p = 0.966). Vascular death was the first event in five patients taking aspirin and in six patients taking ticlopidine (0.7% vs. 0.8%; p = NS); nonfatal AMI in 18 and 8 (2.4% vs. 1.1%; p = 0.049); nonfatal stroke in 3 and 4 (0.4% vs. 0.5%; p = NS); and angina in 33 and 40 (4.5% vs. 5.4%; p = NS), respectively. The frequency of adverse reactions was not significantly different between the two groups. CONCLUSIONS: No difference was found between the ticlopidine and aspirin groups in the rate of the primary combined end point of death, recurrent AMI, stroke and angina.

Usefulness of handgrip to improve ibutilide efficacy in organizing atrial electrical activity during atrial fibrillation.

We analyzed the effect of handgrip on atrial electrical activity during atrial fibrillation (AF) by recording right and left atrial activity in 15 patients with persistent AF under baseline conditions and after saline and ibutilide infusions. The handgrip test for 15 seconds, which was always associated with a significant increase in mean atrial cycle length, was recorded in both atria (right atrium: saline vs saline + handgrip 141 +/- 29 vs 171 +/- 24 ms, p <0.001; ibutilide vs ibutilide + handgrip: 197 +/- 43 vs 221 +/- 39 ms, p <0.005). Handgrip favorably modifies atrial electrophysiologic properties during AF.

Effect of intermittent subdiastolic pressure in thigh cuffs on human arterial baroreflex.

BACKGROUND: We investigated the effects of subdiastolic variations of the pressure inside the thigh cuffs on cardiovascular oscillations and arterial baroreflex sensitivity in humans. METHODS: During 10 min of controlled breathing at low (0.1 Hz) and high (0.25 Hz) frequencies, 30 healthy subjects underwent variations of the pressure inside the thigh cuffs (from 0 to 40 mmHg) at 0.25 and 0.1 Hz respectively; the periods of controlled breathing without cuff pressure modulation were used as a control. The frequency responses of cardiovascular signals were assessed using spectral analysis, and baroreflex sensitivity by the sequence method. RESULTS: Cuff pressure modulation at 0.25 Hz did not affect the RR interval, arterial pressure, or baroreflex sensitivity; at 0.1 Hz it did not change the RR interval and arterial pressure, but engaged (0.76 +/- 0.2 of coherence) and increased the low frequency oscillations of the RR interval (from 5.6 +/- 1 to 6.1 +/- 0.9 ln ms2, p < 0.05) and improved baroreflex sensitivity by 25% (from 14.2 +/- 9 to 17.7 +/- 10 ms/mmHg, p < 0.01). CONCLUSIONS: Subdiastolic thigh cuff pressure modulation at 0.1 Hz improved the low frequency oscillations of heart rate and baroreflex sensitivity. This approach represents a new and simple non-pharmacological strategy for acutely improving baroreflex sensitivity in humans.

Influence of gender and family history of hypertension on autonomic control of heart rate, diastolic function and brain natriuretic peptide.

OBJECTIVE: To verify in a unitary view whether autonomic control of heart rate and cardiac structure and function are modified early in offspring of hypertensive families. METHODS AND RESULTS: We selected 87 age- and sex-matched young normotensive subjects with (n = 45) and without (n = 42) a family history of hypertension who underwent evaluations of arterial pressure, time-domain parameters of autonomic heart rate control (24-h ECG monitoring), spectral baroreflex sensitivity, left ventricular geometry and function (echo-Doppler) and plasma brain natriuretic peptide levels (BNP). The group with a family history of hypertension significantly differed from their counterparts for systolic pressure (119 +/- 11 versus 114 +/- 9 mmHg, P< 0.05), heart rate (RR interval, 766 +/- 64 versus 810 +/- 93 ms, P< 0.05), heart rate variability [the standard deviation of normal RR intervals (SDNN), 147 +/- 29 versus 171 +/- 33 ms, P < 0.051, diastolic function (isovolumetric relaxation time, 65 +/- 9 versus 60 +/- 8 ms, P< 0.05) and BNP (23 +/- 13 versus 37 +/- 10 pg/ml, P< 0.05). Baroreflex sensitivity values did not differ between the two groups. When gender was considered, all the above-mentioned measures, as well as baroreflex sensitivity, were significantly different between males with and without a family history of hypertension but not between females, except for BNP, which was lower in males and females with a history of hypertension (males, 24 +/- 11 versus 38 +/- 8 pg/ml, P< 0.01; females 21 +/- 14 versus 36 +/- 13 pg/ml, P < 0.05). CONCLUSIONS: Male, but not female, hypertensive offspring have modified diastolic function and autonomic control of heart rate; BNP is the only parameter able to characterize hypertensive offspring independently from the influence of gender. This provides the hypothesis that the impaired production of this hormone could play a primary role in the pre-hypertensive state.

Effects of estrogen therapy on arterial resistance and pulsatility in postmenopausal women.

The hypothesis of this study was that changes in arterial determinants of afterload due to static muscular contraction can be modified, in postmenopausal women, by estrogen replacement therapy. Two groups of 14 postmenopausal and 15 premenopausal women were enrolled. Hemodynamic changes induced by right handgrip were recorded between days 7 and 10 of the menstrual cycle in premenopausal women. The same recordings were performed in postmenopausal women, before and after receiving transdermal estrogen replacement therapy for 8 days. Handgrip was performed at 50% of maximal voluntary contraction and maintained until exhaustion. Arterial pressure and blood velocity were recorded in the resting hand with photoplethysmographic and Doppler techniques. Indices of arterial elasticity and resistance were calculated. In postmenopausal women, these indices increased during effort only slightly less after therapy than before, if the mean values and statistical significance were considered, but the most evident effect of therapy was a decrease in interindividual differences in the effort induced changes. This means that, after therapy, increases in arterial resistance and elasticity indices were appreciably prevented mainly in those postmenopausal women who, before therapy, showed the greatest increases. Differences due to therapy were negligible in postmenopausal women in whom, before estrogen replacement, increases in elasticity and resistance indices during effort were similar to those obtained in premenopausal women. After therapy, no differences were found in resting conditions in any of the investigated cardiovascular parameters. Estrogen replacement did not appreciably affect changes in some arterial afterload-related indexes during handgrip, if the average values were considered in a group of postmenopausal women, but uneven and unpredictable peaks in individual responses were cut off, with a better predictability of the responses to sustained muscular contractions, as well as of the related risk factors.

Influence of hydrophilic and lipophilic beta-blockers on heart rate, ventricular repolarization and their interrelationship in normal subjects.

BACKGROUND: It has been hypothesized that hydrophilic and lipophilic beta-blockers have different antiarrhythmic properties because only the latter seem to reduce the rate of sudden death in post-myocardial infarction patients as well as animal models which seem to be independent of their effect on autonomic nervous system modulation. The aim of this study was to evaluate the different effects of a hydrophilic (nadolol) and lipophilic (metoprolol) beta-blocker on ventricular repolarization in normal subjects. METHODS: Seventeen normal subjects entered this randomized, single-blind cross-over study designed to compare the effects of nadolol (80 mg/day) and slow-release metoprolol (200 mg/day) on dynamic ventricular repolarization. The RR intervals, the QT evaluated at the apex (QT apex) and at the end (QT end) of the T wave before and after correction for heart rate, the standard deviation of QT apex and QT end, and the slope of the QT/RR linear relationship (QTa-slope and QTe-slope) were studied using the ELATEC system (ELA Medical, Mountrouge, France), and an evaluation was made of their reproducibility and the effects of each beta-blocker. RESULTS: The most reproducible parameters were QT apex, corrected QT apex and the QTe-slope. Nadolol was associated with a greater adrenergic blockade than metoprolol (lengthening of RR interval +25 +/- 7 and +17 +/- 8% respectively, p = 0.0003) and a lower effect on ventricular repolarization (reduction of corrected QT apex -0.6 +/- 3 and -2.5 +/- 2.1% respectively, p < 0.01; reduction of QTe-slope -5 +/- 16 and -15 +/- 15% respectively, p = 0.03). CONCLUSIONS: At the dosages used in the study, metoprolol showed lower adrenergic blockade but greater effect on ventricular repolarization than nadolol.

Age effect on phase relations between respiratory oscillations of the RR interval and systolic pressure.

Spectral analysis may allow the evaluation of (baroreflex) gain and phase between the RR interval and systolic pressure oscillations synchronous with respiration but, unlike baroreflex gain, the determinants of phase are not completely understood. We evaluated the correlates of spectral phase in 92 healthy subjects (44 men) aged 10-80 years. To do so, the cardiorespiratory signals during paced breathing at 16 breaths/min were continuously recorded and analyzed. In addition, respiratory sinus arrhythmia and baroreflex gain (two indices of cardiac vagal activity) and phase were calculated by using an autoregressive spectral technique. At univariate analysis, the phase correlated with age (r = 0.48, P < 0.001), the RR interval (r = 0.32, P < 0.01), respiratory sinus arrhythmia (r = -0.3, P < 0.01), baroreflex gain (r = -0.29, P < 0.01), and body mass index (r = 0.25, P < 0.05). At multivariate analysis, age was the most important physiological correlate of phase, accounting for 23% of interindividual phase variation. Cardiac vagal activity measures (which were higher in women than men) and the RR interval were also significant independent correlates of phase. We conclude that in addition to the RR interval and cardiac vagal activity, age has a significant impact on the phase relationship between respiratory related oscillations of the RR interval and systolic blood pressure. This spectral measure may contain additional information concerning the mechanisms that influence cardiovascular rhythms.

Respiratory systolic pressure variability during atrial fibrillation and sinus rhythm.

Previous studies have found that respiratory variations of ventricular response in atrial fibrillation are infrequent and inconsistent. This asynchrony between heart rate and respiration may characterize the physiological mechanisms coupling heart rate and systolic blood pressure oscillations in the respiratory band. The aim of this study was to evaluate whether synchronous variations in systolic blood pressure and respiration depend on a simultaneous change in heart rate. Univariate and bivariate spectral analyses were made of the R-R interval, systolic blood pressure, and respiratory signals during controlled respiration (16 breaths/min) in 24 patients with atrial fibrillation before and after efficacious electrical cardioversion and in 24 age- and sex-matched control subjects. During atrial fibrillation, the spectral coherence between respiration and heart rate was low (0.18+/-0.03), but there was a high level of coherence between respiration and systolic blood pressure (0.67+/-0.05). After cardioversion, the coherence between respiration and heart rate increased to 0.86+/-0.04, whereas the geometric mean values of the concomitant respiratory systolic blood pressure oscillations decreased by 72% (from 21.1 to 5.9 mm Hg(2), P<0.001), which was similar to that observed in the control group (5. 7 mm Hg(2)). These results confirm the inconsistent effect of respiration on heart rate response during atrial fibrillation and demonstrate that respiratory sinus arrhythmia is not a prerequisite for systolic blood pressure oscillations but may play an antioscillatory role in respiratory systolic blood pressure variability, which is probably mediated by arterial baroreflex mechanisms.

Automatic activity of a decremental long atrioventricular accessory pathway: an unusual feature.

The electrophysiological properties of decremental atrioventricular and atriofascicular pathways are not completely understood. We report the case of a patient with fast reentrant tachycardia due to a decremental long atrioventricular pathway, who showed a slow automatic tachycardia arising from the same pathway that was successfully eliminated by radiofrequency catheter ablation.

Diastolic dysfunction and baroreflex sensitivity in hypertension.

The determinants of diastolic dysfunction in patients with systemic hypertension are not completely known. To evaluate the possible role of age, arterial blood pressure, and baroreflex heart rate response impairment in causing diastolic dysfunction, we studied 61 patients (42 male; mean+/-SD age, 43.9+/-12 years) with newly recognized and therefore previously untreated systemic hypertension. Diastolic dysfunction was evaluated by means of Doppler echocardiography (and diagnosed as such when the early to atrial peak velocity ratio corrected to heart rate was <1), arterial blood pressure by 24-hour ambulatory monitoring, and baroreflex heart rate response by means of the spectral technique (alpha index) during paced (0.27 Hz) and spontaneous breathing (in a supine position and during tilt). Nineteen patients had diastolic dysfunction, the most powerful predictor of which was age (r=-0.63, P<0.001). The patients with diastolic dysfunction had significantly lower values for spectral baroreflex gain in the high-frequency band than those without (5.2+/-3 versus 8.4+/-5 ms/mm Hg during paced breathing, P<0.05; 7. 4+/-4 versus 13.3+/-7 ms/mm Hg in a supine position, P<0.05; 4.3+/-4 versus 5+/-2 ms/mm Hg during tilt, P

[Radiofrequency transcatheter ablation of a bidirectional decremental accessory atrioventricular pathway in the coronary sinus]. / Ablazione transcatetere mediante radiofrequenza di via accessoria atrioventricolare decrementale bidirezionale in seno coronarico.

We report the case of a 63-year-old patient who underwent radiofrequency catheter ablation of an atrioventricular accessory pathway with bidirectional decremental conduction properties. The successful ablation site was the distal end of a wedge-shaped dilation of the first tract of the coronary sinus. Atrioventricular accessory pathways with anterograde decremental conduction properties was thought to belong to fibers with Mahaim type electrophysiological properties. They rarely show decremental retrograde conduction properties. Most Mahaim type atrioventricular pathways are right-sided with atrial insertion points at various sites along the tricuspid ring. On the other hand, left-sided decrementally conducting accessory pathways are very rare. Mahaim type atrioventricular pathways were never found in the coronary sinus. The bidirectional decremental conduction properties and in particular the anatomic site of the atrioventricular accessory pathway we describe in the present report are both very interesting findings.