Utilizing physiologically based pharmacokinetic modeling to predict theoretically conceivable extreme elevation of serum flecainide concentration in an anuric hemodialysis patient with cirrhosis.

PURPOSE: Higher drug concentrations in complex clinical scenarios in which multiple factors such as drug-drug interactions (DDIs) and comorbidities are simultaneously present are not necessarily rationalized in prospective clinical studies. Physiologically based pharmacokinetic (PBPK) modeling and simulation of the anti-arrhythmic drug flecainide, as an example, were utilized to quantitatively rationalize the higher flecainide concentration in a complex clinical case involving end-stage renal disease (ESRD), cirrhosis, and the co-administration of mexiletine, a CYP1A2 inhibitor. METHODS: The developed flecainide PBPK model was used to evaluate the DDI effect (as measured by AUC ratio before and after inhibition) of mexiletine and the combined disease effects of ESRD and cirrhosis on flecainide exposure. RESULTS: The predicted DDI effect of mexiletine was negligible or weak in anuric hemodialysis with cirrhosis population (mean [5th/95th percentiles], 1.23 [0.97-1.67]), although it was negligible in healthy volunteers (1.03 [1.02-1.05]). The predicted flecainide concentrations after multiple flecainide doses (50 mg BID) in the anuric hemodialysis with cirrhosis population were comparable with the observed value (3602 ng/mL), which fell between the predicted concentrations in the absence and presence of mexiletine (3043 [718-8499] and 5914 [880-20,624] ng/mL, respectively). CONCLUSIONS: The PBPK simulation proposed a likely explanation that the observed higher flecainide concentration could be attributed to the combined effects of ESRD, cirrhosis, and a potential DDI with mexiletine. This approach provides quantitative insight into theoretically conceivable extremes in drug exposure occurring in complex clinical situations even if uncommon.

Radiofrequency Catheter Ablation of Ventricular Tachycardia in Patients With Hypertrophic Cardiomyopathy and Apical Aneurysm.

OBJECTIVES: This study evaluated the characteristics and results of radiofrequency catheter ablation (RFCA) of ventricular tachycardia (VT) in patients with hypertrophic cardiomyopathy (HCM) and left ventricular apical aneurysm (AA). BACKGROUND: Monomorphic VT in patients with HCM and left ventricular AA has been reported. However, outcome data of RFCA are insufficient. METHODS: Fifteen patients with HCM and AA who underwent RFCA for VT at 5 different institutions were included in this study. The data were evaluated retrospectively. RESULTS: Endocardial voltage mapping showed a low-voltage area (LVA), and late potential in the AA was recorded in 12 patients (80%). Although epicardial or intramural origin of VT was suspected in 7 patients, endocardial RFCA successfully suppressed the VT at the LVA border (n = 10) or within the LVA (n = 2). In 2 of 3 patients without LVA at the endocardial site, linear RFCA at the anterior wall of the aneurysmal neck side was successful. In the remaining patient, endocardial RFCA of AA was not effective, and epicardial RFCA site was needed. In all patients, clinical VT became noninducible after RFCA. VT recurrence was observed in 2 patients (13.3%) during the 12-month follow-up period. One patient underwent a second endocardial RFCA, and no VT recurrence was noted. In the other patient, VT recurred 3 months after RFCA and was successfully terminated by antitachycardia pacing of the implantable cardioverter-defibrillator. CONCLUSIONS: In patients with HCM and AA, endocardial RFCA of AA effectively suppressed monomorphic VT which was related to AA and resulted in satisfactory outcomes.

What kinds of factors affect the academic outcomes of university students with mental disorders? A retrospective study based on medical records.

AIMS: University students that suffer from mental disorders seem to have difficulty graduating. Therefore, we investigated risk and protective factors of dropping out with the aim of improving such students' academic outcomes. METHODS: First, we statistically compared the academic outcomes of 203 undergraduate students who received treatment in the Department of Psychiatry of the Tsukuba University Health Center to those of matched controls. Second, clinical factors of 370 mentally ill students were statistically compared between the dropout and graduate groups. RESULTS: Mentally ill students experienced significantly greater difficulties graduating. Furthermore, the ratio of females and the year of study at initial consultation were significantly lower in the dropout group. However, duration of illness, social withdrawal, temporary leaves of absence, percentage of diagnosis of F2, history of truancy, CGI-S/GI score, number of suicide attempts, visits to us, family consultations with us and grade repeating were longer or greater in the dropout group. Ultimately, the number of suicide attempts, CGI-S score, social withdrawal and leaves of absence were significantly associated with dropping out. Moreover, duration of social withdrawal and leaves of absence were significantly correlated with CGI-GI score. CONCLUSION: We found that the number of suicide attempts, CGI-S score, social withdrawal and extended enrollment were risk factors for dropping out, while the therapeutic effect seemed to be a protective factor. As risk factors involved states of social maladjustment, it is necessary not only to treat mental disorders, but also to provide assistance such as educational and individual support for daily living.

Nuclear factor (erythroid derived 2)-like 2 activation increases exercise endurance capacity via redox modulation in skeletal muscles.

Sulforaphane (SFN) plays an important role in preventing oxidative stress by activating the nuclear factor (erythroid derived 2)-like 2 (Nrf2) signalling pathway. SFN may improve exercise endurance capacity by counteracting oxidative stress-induced damage during exercise. We assessed running ability based on an exhaustive treadmill test (progressive-continuous all-out) and examined the expression of markers for oxidative stress and muscle damage. Twelve- to 13-week-old Male wild-type mice (Nrf2 +/+) and Nrf2-null mice (Nrf2 -/-) on C57BL/6J background were intraperitoneally injected with SFN or vehicle prior to the test. The running distance of SFN-injected Nrf2 +/+ mice was significantly greater compared with that of uninjected mice. Enhanced running capacity was accompanied by upregulation of Nrf2 signalling and downstream genes. Marker of oxidative stress in SFN-injected Nrf2 +/+ mice were lower than those in uninjected mice following the test. SFN produced greater protection against muscle damage during exhaustive exercise conditions in Nrf2 +/+ mice than in Nrf2 -/- mice. SFN-induced Nrf2 upregulation, and its antioxidative effects, might play critical roles in attenuating muscle fatigue via reduction of oxidative stress caused by exhaustive exercise. This in turn leads to enhanced exercise endurance capacity. These results provide new insights into SFN-induced upregulation of Nrf2 and its role in improving exercise performance.

Exercise training enhances in vivo clearance of endotoxin and attenuates inflammatory responses by potentiating Kupffer cell phagocytosis.

The failure of Kupffer cells (KCs) to remove endotoxin is an important factor in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). In this study, the effects of exercise training on KC function were studied in terms of in vivo endotoxin clearance and inflammatory responses. Mice were allocated into rest and exercise groups. KC bead phagocytic capacity and plasma steroid hormone levels were determined following exercise training. Endotoxin and inflammatory cytokine levels in plasma were determined over time following endotoxin injection. KC bead phagocytic capacity was potentiated and clearance of exogenously-injected endotoxin was increased in the exercise group. Inflammatory cytokine (TNF-α and IL-6) levels were lower in the exercise group. We found that only DHEA was increased in the plasma of the exercise group. In an in vitro experiment, the addition of DHEA to RAW264.7 cells increased bead phagocytic capacity and attenuated endotoxin-induced inflammatory responses. These results suggest that exercise training modulates in vivo endotoxin clearance and inflammatory responses in association with increased DHEA production. These exercise-induced changes in KC capacity may contribute to a slowing of disease progression in NAFLD patients.

Crucial role of pulmonary vein firing as an initiator of typical atrial flutter: Evidence of a close relationship between atrial fibrillation and typical atrial flutter.

BACKGROUND: Several studies reported that cavotricuspid isthmus-dependent atrial flutter (typical AFL) frequently coexists with atrial fibrillation (AF); however, the underlying mechanisms have not been fully investigated. This study aimed to reveal the mechanisms of the initiation of typical AFL and the association between typical AFL and AF. METHODS: Among 154 consecutive patients undergoing a first catheter ablation of AF, we investigated the appearance and mechanism of spontaneous initiation of typical AFL during catheter ablation. Then, we retrospectively investigated 67 consecutive patients without a previous AF episode who underwent typical AFL ablation. The occurrence and predictors of AF after catheter ablation were evaluated. RESULTS: During AF ablation, spontaneous initiation of typical AFL occurred during sinus rhythm in eight (5.2%) patients. The initiations of typical AFL were pulmonary vein (PV) firings except in one patient, in whom paroxysmal AF following superior vena cava firing initiated reverse typical AFL after PV isolation. After typical AFL ablation, AF occurred in 23 (34.3%) patients (mean follow up, 28.2±20.3 months). Kaplan-Meier analysis showed the occurrence of AF after typical AFL ablation to be significantly higher in the patients with a larger left atrial diameter over 40 mm (log-rank test, P=0.046). CONCLUSIONS: PV firing through AF played an important role in initiating typical AFL. The occurrence of AF after typical AFL ablation was high, and a dilated left atrium was associated with increased occurrence of AF. These findings disclosed the close relationship between typical AFL and AF, especially PV firing.

ß1-Adrenergic receptor Arg389Gly polymorphism affects the antiarrhythmic efficacy of flecainide in patients with coadministration of ß-blockers.

OBJECTIVE: ß1-Adrenergic receptor (ß1-AR) stimulation modulates the antiarrhythmic activities of sodium channel blockers. The ß1-AR Gly389 variant shows a marked decrease in agonist-stimulated cyclic AMP production compared with that of the wild-type Arg389 in vitro. We investigated whether the Arg389Gly polymorphism affects the efficacy of flecainide, a typical sodium channel blocker, in patients with or without coadministration of ß-blockers. METHODS: The effects of the ß1-AR Arg389Gly polymorphism on the antiarrhythmic efficacy of flecainide were compared between with and without coadministered ß-blockers in 159 patients with supraventricular tachyarrhythmia. The antiarrhythmic efficacy of flecainide was assessed for at least 2 months by evaluating symptomatology, 12-lead ECGs, and Holter monitoring results. RESULTS: Genetic differences in the antiarrhythmic efficacy of flecainide were observed in patients with coadministration of ß-blockers. Tachyarrhythmia was well controlled in 60% of Arg389-homozygotes, 30% of Gly389-heterozygotes, and 0% of Gly389-homozygotes (P=0.001). In contrast, no difference in the antiarrhythmic efficacy was observed among the three genotypes in the patients without coadministration of ß-blockers (64, 70, and 60%, respectively). Heart rate in tachyarrhythmia in patients treated with flecainide was significantly higher in Gly389 carriers than in Arg389-homozygotes (P=0.013). CONCLUSION: The Gly389 polymorphism decreased the antiarrhythmic efficacy of flecainide when coadministered with ß-blockers. The results indicate that the Arg389Gly polymorphism may play an important role in predicting the efficacy of flecainide in patients with coadministration of ß-blockers.

Long-Term Prognosis of Brugada-Type ECG and ECG With Atypical ST-Segment Elevation in the Right Precordial Leads Over 20 Years: Results From the Circulatory Risk in Communities Study (CIRCS).

BACKGROUND: Brugada syndrome is recognized as being associated with sudden cardiac death; however, the prevalence of non-type 1 Brugada-type ECG (BrS) or atypical ST-segment elevation in the right precordial leads (STERP) and the long-term prognosis for those patients remain unknown. METHODS AND RESULTS: We analyzed standard 12-lead ECGs of 7178 apparently healthy participants (age range 40-64 years) who underwent health checkups from 1982 to 1986 in the Circulatory Risk in Communities Study, a prospective, large, community-based cohort study in Japan. ECGs with J point amplitude ≥0.2 mV in the right precordial leads were divided into 3 groups: (1) type 1 BrS, (2) type 2 or 3 BrS (non-type 1 BrS), and (3) STERP. The others served as the non-ST-segment elevation group. We identified 8 participants (0.1%) with type1 BrS, 84 (1.2%) with non-type 1 BrS, and 228 (3.2%) with STERP. During a median follow-up of 18.7 years (133 987.0 person-years), sudden cardiac death was observed in no participants (0.0%) with type 1 BrS, in 1 (1.2%) with non-type 1 BrS, in 7 (3.1%) with STERP, and in 50 (0.7%) with non-ST-segment elevation. Participants with STERP had a markedly elevated risk of sudden cardiac death (multivariable hazard ratio 3.9, 95% CI 1.7-9.0). CONCLUSIONS: STERP was associated with an elevated risk of sudden cardiac death in a middle-aged population.

Serum flecainide S/R ratio reflects the CYP2D6 genotype and changes in CYP2D6 activity.

The aims of this study were to clarify whether the ratio of S- to R-flecainide (S/R ratio) in the serum flecainide concentration was associated with the stereoselectivity of flecainide metabolism, and to investigate the effects of the cytochrome P450 (CYP) 2D6 (CYP2D6) genotype and CYP2D6 inhibitor on the serum flecainide S/R ratio. In vitro studies using human liver microsomes and cDNA-expressed CYP isoforms suggested that variability in the serum flecainide S/R ratio was associated with the stereoselectivity of CYP2D6-mediated flecainide metabolism. We examined the serum flecainide S/R ratio in 143 patients with supraventricular tachyarrhythmia. The S/R ratio was significantly lower in intermediate metabolizers and poor metabolizers (IMs/PMs) than in extensive metabolizers (EMs) identified by the CYP2D6 genotype. The cut-off value for the S/R ratio to allow the discrimination between CYP2D6 EMs and IMs/PMs was 0.99. The S/R ratio in patients with co-administration of bepridil, a potent CYP2D6 inhibitor, was lower than 0.99, regardless of the CYP2D6 genotype status. Other factors, including age, sex, body weight, and renal function, did not affect the serum flecainide S/R ratio. This study suggests that the serum flecainide S/R ratio reflects the CYP2D6 genotype and changes in CYP2D6 activity on co-administration of a CYP2D6 inhibitor.

The QRS morphology pattern in V5R is a novel and simple parameter for differentiating the origin of idiopathic outflow tract ventricular arrhythmias.

AIMS: There are many reports on the ECG characteristics of idiopathic outflow tract ventricular arrhythmias (OT-VAs) to predict their origin. However, differentiating near regions using 12-lead ECGs is still complicated. The synthesized 18-lead ECG derived from the 12-lead ECG can provide virtual waveforms of the right-sided chest leads (V3R, V4R, and V5R) and back leads (V7, V8, and V9). The aim of this study was to develop a simple and useful parameter for differentiating OT-VA origins using the 18-lead ECG. METHODS AND RESULTS: We studied 28 and 73 patients with idiopathic VAs in a pacemapping study and validation cohort, respectively. In the pacemapping study, several sites out of five different sites were paced in each patient: the anterior and posterior right ventricular OT (RVOT-ant and RVOT-post), right and left coronary cusps (RCC and LCC), and junction of both cusps (RLJ). The 18-lead ECGs during pacemapping among the five sites were compared for establishing a simple parameter to predict VA origins. A novel parameter using 18-lead ECGs was tested prospectively in 73 patients. In the pacemapping study, the dominant QRS morphology pattern in the synthesized V5R significantly differed among those sites (RVOT-ant:Rs, RVOT-post:rS, RCC:QS, RLJ:qR, and LCC:R). The patients in the validation cohort were divided into five groups depending on those QRS morphology patterns during VAs in the synthesized V5R. Each V5R QRS morphology pattern could predict a precise origin of the OT-VAs with an overall accuracy of 75%. CONCLUSION: The QRS morphology pattern in V5R was a simple and useful parameter for differentiating detailed OT-VA origins.

Prognosis of myocardial infarction with left ventricular dysfunction in the coronary revascularization era.Subanalysis of the Japanese Coronary Artery Disease (JCAD) Study.

BACKGROUND: Indications of implantable cardioverter-defibrillator (ICD) for patients with an old myocardial infarction (OMI) and left ventricular dysfunction (LVD) were expanded in Western countries after the results of MADIT II. However, the prognosis of OMI patients with LVD and the merits of prophylactic implantation of ICD, based on evidence in Japan, have not yet been clarified. This subanalysis of the Japanese Coronary Artery Disease (JCAD) Study focused on MADIT II-compatible patients to clarify the prognosis of OMI patients with LVD in Japan. METHODS AND RESULTS: Consecutive 6,868 OMI patients were prospectively followed up for 3 years or until clinical events occurred. 291 patients had left ventricular ejection fraction (LVEF) ≤30%. Clinical events, congestive heart failure, cardiopulmonary arrest on arrival and vascular events were significantly more frequent in patients with LVEF ≤30% than in those with better LVEF. In the LVEF ≤30% group, cardiopulmonary arrest on arrival comprised 33% of all-cause deaths, and the survival curves at 2 years of the LVEF ≤30% group were almost compatible with those of the MADIT II ICD group. CONCLUSIONS: In this subanalysis, LVD was less frequent than in Western countries. The annual death rate in JCAD was better than for the MADIT II ICD group. The prophylactic use of ICD seemed to be less effective than in Western countries but still expected to be useful for OMI patients with LVD in Japan.

Involvement of peptidyl-prolyl isomerase Pin1 in the inhibitory effect of fluvastatin on endothelin-1-induced cardiomyocyte hypertrophy.

AIMS: Cardiac hypertrophy is elicited by endothelin (ET)-1 as well as other neurohumoral factors, hemodynamic overload, and oxidative stress; HMG-CoA reductase inhibitors (statins) were shown to inhibit cardiac hypertrophy partly via the anti-oxidative stress. One of their common intracellular pathways is the phosphorylation cascade of MEK signaling. Pin1 specifically isomerizes the phosphorylated protein with Ser/Thr-Pro bonds and regulates their activity through conformational changes. There is no report whether the Pin1 activation contributes to ET-1-induced cardiomyocyte hypertrophy and whether the Pin1 inactivation contributes to the inhibitory effect of statins. The aim of this study was to reveal these questions. MAIN METHODS: We assessed neonatal rat cardiomyocyte hypertrophy using ET-1 and fluvastatin by the cell surface area, ANP mRNA expression, JNK and c-Jun phosphorylation, and [(3)H]-leucine incorporation. KEY FINDINGS: Fluvastatin inhibited ET-1-induced increase in the cell surface area, ANP expression, and [(3)H]-leucine incorporation; and it suppressed the signaling cascade from JNK to c-Jun. The phosphorylated Pin1 level, an inactive form, was decreased by ET-1; however, it reached basal level by fluvastatin. Furthermore, Pin1 overexpression clearly elicited cardiomyocyte hypertrophy, which was inhibited by fluvastatin. SIGNIFICANCE: This is the first report that ET-1-induced cardiomyocyte hypertrophy is mediated through the Pin1 activation and that the inhibitory effect of fluvastatin on cardiomyocyte hypertrophy would partly be attributed to the suppression of the Pin1 function. This study firstly suggests that Pin1 determines the size of hypertrophied cardiomyocyte by regulating the activity of phosphorylated molecules and that statins exert their pleiotropic effects partly via Pin1 inactivation.

Stereoselective analysis of flecainide enantiomers using reversed-phase liquid chromatography for assessing CYP2D6 activity.

Stereoselective analyses of flecainide enantiomers were performed using reversed-phase high-performance liquid chromatography (HPLC) equipped with a polysaccharide-based chiral column (Chiralpak AS-RH) and fluorescence detector. Excitation and emission wavelengths were set at 300 and 370 nm, respectively. Flecainide enantiomers in serum and urine were extracted using diethyl ether. The mobile phase solution, comprising 0.1 m potassium hexafluorophosphate and acetonitrile (65:35, v/v), was pumped at a flow rate of 0.5 mL/min. The recoveries of flecainide enantiomers were greater than 94%, with the coefficients of variation (CVs) <6%. The calibration curves of flecainide enantiomers in serum and urine were linear in the concentration range 5-500 ng/mL and 0.75-15 µg/mL (r > 0.999), respectively. CVs in intra-day and inter-day assays were 1.8-5.8 and 3.4-7.5%, respectively. In a pharmacokinetic study, the ratios of (S)- to (R)-flecainide (S/R ratio) in the area under the curve and the amount of flecainide enantiomers excreted in urine were lower in a subject carrying CYP2D6*10/*10 than in subjects carrying CYP2D6*1/*2. The S/R ratio of trough serum flecainide concentration ranged from 0.79 to 1.16 in patients receiving oral flecainide. The present HPLC method can be used to assess hepatic flecainide metabolism in a pharmacokinetic study and therapeutic drug monitoring.

SCN5A promoter haplotype affects the therapeutic range for serum flecainide concentration in Asian patients.

OBJECTIVE: An increased slowing of cardiac conduction induced by sodium channel blockers is remarkably observed in carriers of an Asian-specific promoter haplotype [haplotype B (HapB)] of the cardiac sodium channel gene (SCN5A). We investigated the effect of HapB on the therapeutic range for serum flecainide concentration in Asian patients. PATIENTS AND METHODS: We examined the serum concentration and antiarrhythmic efficacy of flecainide, together with the SCN5A promoter haplotype, in 146 patients with supraventricular tachyarrhythmias. Trough serum flecainide concentrations were determined by HPLC. The antiarrhythmic efficacy of flecainide was assessed for at least 2 months through examination of symptomatology, ECG, and Holter monitoring. RESULTS: The serum flecainide concentration did not differ between the wild-type HapA homozygotes and HapB carriers under treatment with the usual dose. A genetic difference in the antiarrhythmic efficacy of flecainide was observed between the HapA homozygotes and HapB carriers at serum flecainide concentrations less than 300 ng/ml (42.9 vs. 68.8%; P=0.022). PR prolongation and QRS widening were observed more commonly among the HapB carriers with serum flecainide concentrations of at least 300 ng/ml than in the HapA homozygotes (PR, 210 ± 25 vs. 195 ± 25 ms; P=0.036; and QRS, 112 ± 10 vs. 105 ± 9 ms; P=0.030). CONCLUSION: These findings suggest that the therapeutic range for serum flecainide concentration is lower in HapB carriers than in HapA homozygotes.

CYP2D6 genotype affects age-related decline in flecainide clearance: a population pharmacokinetic analysis.

OBJECTIVE: To investigate the association between age-related decline in flecainide clearance and CYP2D6 genotype, we conducted a population pharmacokinetic analysis of flecainide using routine therapeutic drug monitoring data. METHODS: Population pharmacokinetic analysis was performed on retrospective data from 163 genotyped patients treated with oral flecainide for supraventricular tachyarrhythmias. The CYP2D6 genotype was categorized as CYP2D6 homozygous extensive metabolizers (hom-EMs; n=57), heterozygous extensive metabolizers (het-EMs; n=79), and intermediate metabolizers and poor metabolizers (IMs/PMs; n=27). RESULTS: Population pharmacokinetic analysis revealed that estimated glomerular filtration rate, body weight, female sex, and aging were important factors for estimating flecainide clearance. The metabolic clearance was decreased age dependently in a curvilinear fashion, where the lower clearance was observed in greater than 60 years for het-EMs and greater than 55 years for IMs/PMs. The reduction in metabolic clearance in elderly (70 years) patients compared with middle-aged (52 years) patients was different among the CYP2D6 genotype groups: 22.1 and 49.5% in CYP2D6 het-EMs and IMs/PMs, respectively, and no change in hom-EMs. A 11.4% reduction in estimated glomerular filtration rate in elderly patients compared with middle-aged patients corresponded to 6.1% decline in flecainide clearance. Overall, the age-related decline in flecainide clearance was 6.1% in hom-EMs, 16.3% in het-EMs, and 28.9% in IMs/PMs groups. CONCLUSION: This study suggests that CYP2D6 genotype is a determinant factor of age-related decline in flecainide clearance.

Increased plasma levels of big-endothelin-2 and big-endothelin-3 in patients with end-stage renal disease.

AIMS: Big endothelins (pro-endothelin; inactive-precursor) are converted to biologically active endothelins (ETs). Mammals and humans produce three ET family members: ET-1, ET-2 and ET-3, from three different genes. Although ET-1 is produced by vascular endothelial cells, these cells do not produce ET-3, which is produced by neuronal cells and organs such as the thyroid, salivary gland and the kidney. In patients with end-stage renal disease, abnormal vascular endothelial cell function and elevated plasma ET-1 and big ET-1 levels have been reported. It is unknown whether big ET-2 and big ET-3 plasma levels are altered in these patients. The purpose of the present study was to determine whether endogenous ET-1, ET-2, and ET-3 systems including big ETs are altered in patients with end-stage renal disease. MAIN METHODS: We measured plasma levels of ET-1, ET-3 and big ET-1, big ET-2, and big ET-3 in patients on chronic hemodialysis (n=23) and age-matched healthy subjects (n=17). KEY FINDINGS: In patients on hemodialysis, plasma levels (measured just before hemodialysis) of both ET-1 and ET-3 and big ET-1, big ET-2, and big ET-3 were markedly elevated, and the increase was higher for big ETs (Big ET-1, 4-fold; big ET-2, 6-fold; big ET-3: 5-fold) than for ETs (ET-1, 1.7-fold; ET-3, 2-fold). SIGNIFICANCE: In hemodialysis patients, plasma levels of the inactive precursors big ET-1, big ET-2, and big ET-3 levels are markedly increased, yet there is only a moderate increase in plasma levels of the active products, ET-1 and ET-3. This suggests that the activity of endothelin converting enzyme contributing to circulating levels of ET-1 and ET-3 may be decreased in patients on chronic hemodialysis.

Endothelin-1-induced cardiomyocyte hypertrophy is partly regulated by transcription factor II-F interacting C-terminal domain phosphatase of RNA polymerase II.

AIMS: Cardiac hypertrophy is associated with the increase of total amount of RNA, which is in accordance with RNA polymerase II (RNAPII) activation via C-terminal domain (CTD) phosphorylation of the largest subunit of RNAPII. It has been demonstrated that endothelin-1 (ET-1) phosphorylates CTD at the hypertrophic response in cardiomyocytes. However, it is unclear whether ET-1-induced hypertrophy is affected by the CTD phosphatase, transcription factor IIF-interacting CTD phosphatase1 (FCP1). MAIN METHODS: We analyzed whether ET-1-induced cardiomyocyte hypertrophy was affected by overexpression of FCP1 or dominant-negative form of FCP1 (dnFCP1) in neonatal rat cardiomyocytes. KEY FINDINGS: The level of ET-1-induced RNAPII CTD phosphorylation was decreased by FCP1 overexpression, whereas it was sustained by dnFCP1. Global RNA synthesis evaluated by [(3)H]-uridine incorporation showed that the ET-1-induced increase in RNA synthesis was suppressed by FCP1 and was augmented by dnFCP1. ET-1-induced increase in cell surface area was suppressed by FCP1 and was preserved by dnFCP1. Furthermore, the ET-1-induced increase in molecular markers of cardiac hypertrophy, expression of ANP and ß-MHC gene, was suppressed by FCP1 and was not inhibited by dnFCP1. SIGNIFICANCE: ET-1-induced cardiac hypertrophy and CTD phosphorylation level are functionally regulated by FCP1. These findings suggest that FCP1 plays an important role in ET-1-induced cardiac hypertrophy via controlling phosphorylation level of the RNAPII CTD.

Electrocardiographic determinants of the polymorphic QRS morphology in idiopathic right ventricular outflow tract tachycardia.

INTRODUCTION: Premature ventricular contractions (PVCs) arising from the right ventricular outflow tract (RVOT) can trigger polymorphic ventricular tachycardia (PVT) or ventricular fibrillation (VF) in patients with no structural heart disease. We aimed to clarify the ECG determinants of the polymorphic QRS morphology in idiopathic RVOT PVT/VF. METHODS AND RESULTS: The ECG parameters were compared between 18 patients with idiopathic PVT/VF (PVT-group) and 21 with monomorphic VT arising from the RVOT (MVT-group). The coupling interval (CI) of the first VT beat was comparable between the 2 groups. However, the prematurity index (PI) of the first VT beat was smaller in the PVT-group than in the MVT-group (P < 0.001). Furthermore, the QT index, defined as the ratio of the CI to the QT interval of the preceding sinus complex, was also smaller for the PVT/VF in the PVT-group than that for the VT in the MVT-group (P < 0.01). In the PVT-group, the CI of the first VT beat was comparable between that of VT and isolated PVCs, but the PI of the first VT beat was shorter for VT than isolated PVCs (P < 0.05). The PI was the only independent determinant of the polymorphic QRS morphology (odd ratio = 2.198; 95% confidence interval = 1.321-3.659; P = 0.002). CONCLUSION: The smaller PIs of the first VT beat may result in a polymorphic QRS morphology.