An investigation of visual hallucinations associated with voriconazole administration to patients with hematological malignancies.

Voriconazole (VRCZ) is commonly administered to treat fungal infections in patients with hematological malignancies. Some of these patients experience VRCZ-associated visual hallucinations. We conducted a retrospective survey to investigate the characteristic features of this side effect. Patients with hematological malignancies who were treated with VRCZ for a fungal infection after hospitalization at Ichinomiya municipal hospital between 1 October 2005 and 31 December 2015 were included in this study (n = 103). Fifteen of these (14.6%) reported visual hallucinations that started on day 1-7. Seven of these 15 patients developed this symptom rapidly (day 1 or 2). Three patients had transient symptoms (lasting 2-12 days), 6 patients experienced hallucinations throughout the treatment, and the duration was unknown in 6 patients. Eleven patients experienced visual hallucinations when their eyes were closed (73 %) and these disappeared when they opened their eyes. One patient had visual hallucinations with open eyes, while the state of the eyes was unknown in 3 patients. The patients saw a range of images including people, animals, landscapes, and foods; several reported seeing images like those found in movies. In addition, 9 of 15 patients (60%) with visual hallucinations had visual disturbances. This was a higher proportion than that observed in patients who did not develop hallucinations (17 of 88; 19.3 %; P < 0.05). However, we found no significant difference between the blood VCRZ concentrations of patients who developed or did not develop visual hallucinations. This study indicated that most of these patients had visual hallucinations that manifested on eye closure, and they did not progress to serious mental illness. Our findings emphasized the importance of fully explaining the features of this symptom to each patient prior to starting VRCZ administration in order to reduce anxiety. In addition, since VRCZ discontinuation will compromise patient management, therapeutic drug monitoring should be used to increase the likelihood of successful therapy.

Case report: alternating exit sites in reentry circuit of ventricular tachycardia with nonischemic cardiomyopathy - relationship between ablation site and inner loop.

We present a patient with nonischemic cardiomyopathy who had ventricular tachycardia (VT) with QRS morphology alternans. VTs of two QRS morphologies (VT1 and VT2) exhibiting a right bundle branch block pattern with inferior axis was induced by ventricular pacing. The morphology of the QRS complex during VT1 exhibited more distinctively inferior axis than those during VT2. Induced VTs had similar morphologies to clinically the documented VTs. Pacemapping at anterolateral site of the left ventricle during sinus rhythm produced the same QRS complex of VT1 in a surface 12-lead electrocardiogram. A mapping study was performed with an electrode catheter located at the same site of LV during sustained VT1. The analysis of the local electrograms and postpacing interval during concealed entrainment at the catheter mapping revealed this pacing site was at the inner loop of the reentry circuit. Radiofrequency catheter ablation was performed at this site. The morphology of VT1 changed to different QRS morphology (VT2) during the first delivery of radiofrequency energy and was terminated after 20 seconds of the application. Then VT with alternans of QRS morphology and cycle length of VT1 and VT2 was induced by ventricular pacing, and was abolished by the second application of radiofrequency energy at this same site, suggesting that this site was located in the exit site close to inner loop of the reentry circuit and the alternans of QRS morphology was linked to the change of exit site.

Spontaneous regression over a 16-year period of tachyarrhythmias to sick sinus syndrome and complete atrioventricular block in a young patient with Ebstein's anomaly.

A 25-year-old man with Ebstein's anomaly showed spontaneous regression of tachyarrhythmias to sick sinus syndrome and complete atrioventricular block over a 16-year period. This is the first clinical report supporting the hypothesis that abnormal cell death might contribute to the disturbance of the heart conduction system in Ebstein's anomaly.

Polymorphic ventricular tachycardia in patients with vasospastic angina--clinical and electrocardiographic characteristics and long-term outcome.

There have been few clinical studies exploring the characteristics of spontaneous polymorphic ventricular tachycardia (VT) during a vasospastic angina attack. During a 4-year recruitment period, Holter ECG recordings were monitored for 42+/-24 h during a drug-free period in 60 consecutive patients with vasospastic angina (VSA) and of these, 8 patients had at least one episode of polymorphic VT during monitoring. Ischemic ST segment elevation was immediately preceded the spontaneous polymorphic VT in all 8 patients, 4 of whom had silent coronary vasospasm. Immediately before the onset of polymorphic VT, both R-on-T and long-short sequences were observed in 4 of the 8 patients and ST wave alternans were recorded in 2 patients. VT exhibited a pattern of torsade de pointes in 4 of the 8 patients. Five patients underwent electrophysiologic testing during a drug-free asymptomatic phase, and polymorphic VT was induced in 2 of the 5 patients, with one developing ventricular fibrillation. During a follow-up period of 73+/-17 months, there was a significant difference in the incidence of sudden death between patients with and without VT (2/8 cases [25%] vs 0/52 [0%]; p<0.01). Thus, vasospastic attacks, even if asymptomatic, that immediately precede the development of polymorphic VT may be associated with a repolarization abnormality and an increased risk of sudden death.

Assessment of noninvasive markers in identifying patients at risk in the Brugada syndrome: insight into risk stratification.

OBJECTIVES: The aim of this study was to compare the use of various noninvasive markers for detecting risk of life-threatening arrhythmic events in patients with Brugada syndrome. BACKGROUND: The role of conduction disturbance in arrhythmogenesis of the syndrome is controversial, whereas it is well established that repolarization abnormalities are responsible for arrhythmias. The value of noninvasive markers reflecting conduction or repolarization abnormalities in identifying patients at risk for significant arrhythmias has not been shown. METHODS: We assessed late potentials (LP) using signal-averaged electrocardiography (ECG), microvolt T-wave alternans (TWA), and corrected QT-interval dispersion (QTD) in 44 consecutive patients who had ECGs showing a pattern of right bundle branch block and ST-segment elevation in leads V1 to V3 but structurally normal hearts. The patients were compared with 30 normal individuals. RESULTS: Eleven patients were excluded from data analysis because of an absence of ECG manifestations of Brugada syndrome at the time of the tests. A history of life-threatening events defined as syncope and aborted sudden death was present in 19 of 33 patients (58%); in 15 of the 19 patients, stimulation induced ventricular fibrillation or polymorphic ventricular tachycardia. The LP were present in 24 of 33 patients (73%); TWA were present in 5 of 31 patients (16%); and a QTD >50 ms was present in 9 of 33 patients (27%). The incidence of LP in Brugada patients was significantly (p < 0.0001) higher than in the controls, whereas incidences of TWA and QTD were not significantly different. Multivariate logistic regression analysis revealed that the presence of LP had the most significant correlation to the occurrence of life-threatening events (p = 0.006). CONCLUSIONS: Late potentials are a noninvasive risk stratifier in patients with Brugada syndrome. These results may support the idea that conduction disturbance per se is arrhythmogenic.

Correlation of genetic etiology with response to beta-adrenergic blockade among symptomatic patients with familial long-QT syndrome.

Mutations in any of the five genes KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A can be responsible for familial long QT syndrome (LQTS), an arrhythmogenic disorder that entails a high risk of sudden death. beta-Adrenergic blocking agents are the first therapeutic choice, and 80% of patients treated with these agents show symptomatic relief; however the remaining 20% do not respond well. We previously performed a nationwide analysis of familial long QT syndrome (LQTS) in Japan and identified 32 mutations in the KCNQ1 and KCNH2 genes. In the present retrospective study, we found that patients carrying mutations in the KCNQ1 gene responded better to beta-adrenergic blocking agents than those with KCNH2 mutations (12 of 13 vs 1 of 5; P = 0.0077, Fisher's exact test). This is a good example of the power of genetic diagnosis to direct the selection of appropriate therapy for patients with diseases of heterogeneous genetic etiology.

Diagnosis of carotid artery atheroma by magnetic resonance imaging.

Atheroma appears as a very low signal intensity area on 2-dimensional time-of-flight (TOF) magnetic resonance (MR) images, and its components have various signal intensities on spin-echo (SE) images. The present study investigated atheroma of the carotid arteries in 37 subjects with risk factors (63+/-10 years of age; 19 men) by magnetic resonance imaging (MRI). On 2-dimensional (2D) TOF images, the carotid arteries were clearly demonstrated in all cases and atheroma was detected in 23 patients. The most common location of atheroma was at the origin of the internal carotid artery. There was vascular remodeling in all patients with atheroma. 2D-TOF images showed 97% agreement with ultrasonography. SE images clearly demonstrated atheroma in all 23 patients with atheroma. All patients with atheroma showing high signal intensity on T1-weighted images had hyperlipidemia. These findings indicate that the 2D-TOF imaging method is useful for detecting atheroma and SE-images are useful for its characterization.

Evaluation of flow volume and flow patterns in the patent false lumen of chronic aortic dissections using velocity-encoded cine magnetic resonance imaging.

In 21 patients with chronic aortic dissections and proven patent false lumens, the flow volume and flow patterns in the patent false lumens was evaluated using velocity-encoded cine magnetic resonance imaging (VENC-MRI) and the relationship between the flow characteristics and aortic enlargement was retrospectively examined. Flow patterns in the false lumen were divided into 3 groups: pattern A with primarily antegrade flow (n=6), pattern R with primarily retrograde flow (n=3), and pattern B with bidirectional flow (n=12). In group A, the rate of flow volume in the false lumen compared to the total flow volume in true and false lumens (%TFV) and the average rate of enlargement of the maximum diameter of the dissected aorta per year (deltaD) were significantly greater than in groups R and B (%TFV: 74.1+/-0.07 vs 15.2+/-0.03 vs 11.8+/-0.04, p<0.01; deltaD: 3.62+/-0.82 vs 0 vs 0.58+/-0.15 mm/year, p<0.05, respectively). There was a significant correlation between %TFV and deltaD (r=0.79, p<0.0001). Evaluation of flow volume and flow patterns in the patent false lumen using VENC-MRI may be useful for predicting enlargement of the dissected aorta.

A novel SCN5A mutation associated with idiopathic ventricular fibrillation without typical ECG findings of Brugada syndrome.

Mutations in the human cardiac Na+ channel alpha subunit gene (SCN5A) are responsible for Brugada syndrome, an idiopathic ventricular fibrillation (IVF) subgroup characterized by right bundle branch block and ST elevation on an electrocardiogram (ECG). However, the molecular basis of IVF in subgroups lacking these ECG findings has not been elucidated. We performed genetic screenings of Japanese IVF patients and found a novel SCN5A missense mutation (S1710L) in one symptomatic IVF patient that did not exhibit the typical Brugada ECG. Heterologously expressed S1710L channels showed marked acceleration in the current decay together with a large hyperpolarizing shift of steady-state inactivation and depolarizing shift of activation. These findings suggest that SCN5A is one of the responsible genes for IVF patients who do not show typical ECG manifestations of the Brugada syndrome.

[Treatment of choice and long-term prognosis for ventricular arrhythmias].

Treatment of choice and long-term prognosis of the patients with ventricular arrhythmias are described in terms of prevention of sudden cardiac death and/or recurrence of life-threatening arrhythmias(ventricular tachycardia and ventricular fibrillation). 1) As to the long-term prognosis of ventricular tachyarrhythmias, presence of organic heart disease and degree of cardiac dysfunction are major determining factors. 2) The prognosis of patients with ventricular arrhythmias depends on how sudden cardiac death and life-threatening arrhythmias can be prevented. Among various methods, the electrophysiological test and its guided-therapy for antiarrhythmic drugs are now believed to be the most effective method for the prediction and prevention of the life-threatening events. We propose that the signal averaged electrocardiography is the best screening method as non-invasive approach for the selection of patients undergoing the electrophysiological test. 3) There are still certain limitations as to the prediction of sudden cardiac death and/or prevention of recurrent life-threatening arrhythmias by antiarrhythmic drug treatments in the certain numbers of patients depending on their basal cardiac disease and functional impairment. At present, catheter ablation procedure and implantable cardioverter defibrillator are the choice of the treatment in these cases. 4) In addition to conventional antiarrhythmic drugs, the treatment for the basal cardiac condition is mandatory for the long-term prognosis in the patients with ventricular arrhythmias.

[The effects of propofol anesthesia with or without the use of nitrous oxide on the intraoperative involuntary movement, the postoperative awareness and vomiting].

The authors investigated the effect of anesthesia with nitrous oxide and propofol on intraoperative involuntary movement, muscle relaxant usage, postoperative nausea and vomiting, the total amount of propofol used, and recovery time from anesthesia. Eighty-eight patients for gynecological surgery were randomly divided into group PE: propofol/epidural (n = 44), and group PEG: propofol/epidural/nitrous oxide (n = 44). The frequency of postoperative nausea and vomiting were assessed at 24-h postoperatively by blinded observers. There were significant decreases of the mean amounts of propofol and muscle relaxant used between group PEG and group PE. The authors found no correlation between the use of nitrous oxide and intraoperative involuntary movement, subsequent development of postoperative quality of awareness, recovery time, nausea and vomiting. We recommend PEG method for gynecological surgery rather than PE from an economical viewpoint because it is associated with the reduction of mean propofol and muscle relaxant used.

Voltage-shift of the current activation in HERG S4 mutation (R534C) in LQT2.

OBJECTIVE: Recently, a novel missense mutation (R534C) in the S4 region of human ether-a-go-go-related gene (HERG) was identified in one Japanese LQT2 family. The S4 region presumably functions as a voltage sensor. However, it has not yet been addressed whether the S4 region of HERG indeed functions as a voltage sensor, and whether these residues play any role in abnormal channel function in cardiac repolarization. METHODS: We characterized the electrophysiological properties of the R534C mutation using the heterologous expression system in Xenopus oocytes. Whole cell currents were recorded in oocytes injected with wild-type cRNA, R534C cRNA, or a combination of both. RESULTS: Clinical features--QTc intervals of all affected patients with R534C mutation in HERG are prolonged ranging from 460 to 680 ms (averaged QTc interval > 540 ms). One member of this family had experienced sudden cardiac arrest, and other suffered from recurrent palpitation. Electrophysiology--Oocytes injected with R534C cRNA did express functional channels with altered channel gating. Kinetic analyses revealed that the R534C mutation shifted the voltage-dependence of HERG channel activation to a negative direction, accelerated activation and deactivation time course, and reduced steady-state inactivation. Quantitative analyses revealed that this mutation did not cause apparent dominant-negative suppression. Computer simulation--Incorporating the kinetic alterations of R534C, however, did not reproduce prolonged action potential duration (APD). CONCLUSIONS: The data revealed that arginine at position 534 in the S4 region of HERG is indeed involved in voltage-dependence of channel activation as a voltage sensor. Our examination indicated that HERG current suppression in R534C mutation was the least severe among other mutations that have been electrophysiologically examined, while affected patients did show significant QT prolongation. This suggest that another unidentified factor(s) that prolong APD might be present.

Significance of abnormal root mean square voltages in signal averaged electrocardiogram as a reliable predictor of sustained ventricular tachycardia.

The late potential is useful to predict patients with sustained ventricular tachycardia (VT). However, because positive predictive value for sustained VT is low, the validity of late potential for screening the patients to be studied by electrophysiological tests was not high. We examined 923 cases, including 63 cases of sustained VT. When we separated patients showing abnormal values of the root mean square voltage of the QRS end part 40 milliseconds (RMS40) into four groups, there was a tendency of a higher incidence of sustained VT with lower value of RMS40. When we conducted electrophysiological tests on 121 cases without sustained VT, it turned out a high induction rate of sustained VT in patients with low RMS40 values (RMS40 < 10 microV, 67%; < 20 microV, 30%; 20 microV, < or = 5%). We conclude abnormally low value (less than 10 microV) of RMS40 can be useful for screening the late potential-positive cases who are high risk for inducible sustained VT.

Genomic organization and mutational analysis of HERG, a gene responsible for familial long QT syndrome.

Familial long QT syndrome (LQTS) is characterized by prolonged ventricular repolarization. Clinical symptoms include recurrent syncopal attacks, and sudden death may occur as a result of ventricular tachyarrhythmias. Three genes responsible for this syndrome (KVLQT1, HERG, and SCN5A) have been identified so far, and mutations have been reported on the basis of partially characterized genomic organization. To optimize the search for HERG mutations, we have determined the genomic structure of HERG and investigated mutations in LQTS families. Human genomic clones containing the HERG gene were isolated from a human genomic library by using reverse-transcribed polymerase chain reaction (RT-PCR) products from this gene as probes. We determined exon/intron boundaries and flanking intronic sequences by using primers synthesized on the basis of the HERG cDNA sequence available in the DNA database. HERG was shown to consist of 15 exons spanning approximately 19 kb on chromosome 7q35. Subsequently, we synthesized oligonucleotide primers to cover the entire coding region and searched for mutations in 36 Japanese LQTS families. When genomic DNA from each proband was examined by the PCR/single-strand conformation polymorphism technique followed by direct DNA sequencing, five novel mutations were detected. Each mutation was present in affected relatives of the respective proband. This work should increase the efficiency of screening mutations associated with HERG.

Supernormal conduction in a case of Mobitz type II atrioventricular block.

A 52-year-old woman exhibited Mobitz type II atrioventricular block with right bundle branch block and 1:1 atrioventricular conduction at or slower than 80 beats/min. Electrophysiologic study revealed transient HV interval block followed by recovery from the block at shorter coupling intervals without prolongation of the H1H2 and H2V2 intervals, suggesting true supernormal conduction. Isoproterenol enhanced the supernormal conduction, with shortening of blocked intervals and recovery of atrioventricular conduction, while atropine caused their less marked enhancement. Linking (ie, retrograde concealment of the impulse to the distal His bundle region through the blocked right bundle branch) is considered a possible mechanism of supernormal conduction in this case.

Non-dipolarity of heart potentials estimated by magnetocardiography in normal subjects.

We studied non-dipolarity characteristics during ventricular excitation in normal adults and children by magnetocardiography (MCG) by recording magnetic field on the thorax. The source and currents of the electrical dipole from the onset up to 60 ms of ventricular excitation were analyzed in 16 adults and 5 children. A single equivalent current dipole (ECD) was estimated by Sarvas' formula for the sphere model at 1 ms intervals. The non-dipole value (NDV) was calculated from the magnetic field strength at each recording point and theoretically estimated by ECD, representing an index for the non-dipolarity. At 32-34 ms from the beginning of QRS, the mean NDV was a minimum in all subjects suggesting at least a non-dipole component during this period. High NDV (over 5%) were present in most subjects in both the early and late phase compared to this period. Thirteen of 16 adults had a high NDV in the early phase (9.3 +/- 3.0%, mean +/- SD) and all 16 subjects had a high NDV in the late phase (21.5 +/- 10.5%). All 5 children had high NDV in both the early (10.5 +/- 5.4%) and late phases (16.8 +/- 7.9%). A single ECD estimation by MCG showed a relatively low non dipolar component and MCG could be applied to the clinical evaluation of cardiac excitation in both normal and pathological conditions.

Increase in heart rate after radiofrequency catheter ablation is mediated by parasympathetic nervous withdrawal and related to site of ablation.

To assess the mechanism for the increased sinus rate after radiofrequency catheter ablation performed for atrioventricular nodal reentrant tachycardia (AVNRT), we studied heart rate variability before and after radiofrequency catheter ablation in 17 patients with AVNRT and in 38 patients with an accessory pathway. The accessory pathway was located at the left ventricular free wall, the right ventricular free wall, or the posterior interventricular septum. An increased sinus rate was observed in patients with AVNRT or with the accessory pathway at the posterior septum or left free wall after radiofrequency ablation. In these groups, high-frequency power, root mean square of successive difference and percent of adjacent cycles that were more than 50 ms apart, all of which are indices reflecting parasympathetic nervous activity, were decreased. The ratio of low-frequency to high-frequency power reflecting sympathovagal balance, was increased in patients with AVNRT or with an accessory pathway at the posterior septum or left free wall. Increases in sinus rate were correlated with decreases in high-frequency power, and percent of adjacent cycles more than 50 ms apart that the increase in heart rate was due to parasympathetic nervous withdrawal.