渡邉 英一

Subjects and Methods: We included 217 patients with 338 PAF (79 SHD patients with 131 episodes; 138 NSHD patients with 207 episodes). The probabilities for the onset, maintenance and termination of PAF for each hour were analyzed using Holter monitoring data and harmonic models being fitted into a cosinusoidal function. Results: The SHD group had a triphasic circadian pattern at the onset with higher peaks at midnight, in the early morning and in the late afternoon (p < 0.05), whereas the NSHD group showed a single peak at midnight (p < 0.01). The probability of maintenance revealed a single peak during midnight (SHD, p < 0.0001; NHD, p < 0.01). The termination showed a peak at noon in the SHD group (p < 0.05), whereas there was a double peak at 10:00 am and 8:00 pm in the NSHD group (p = 0.06). RR intervals just after the PAF onset showed marked shortening in the daytime initiation PAF as compared to the nighttime initiation PAF in both SHD and NSHD groups (p < 0.01). Conclusion: These observations suggest that the SHD group has very complex onset hours, whereas the NSHD group shows complex termination hours. Reflexly accelerated sympathetic tone just after the PAF onset is suggested in the daytime initiation PAF. Ann Noninvasive Electrocardiol 2009;14(3):280-289.

BACKGROUND Morbidity and mortality due to chronic heart failure remain unacceptably high despite effective drug therapies, and the search for a better risk predictor is ongoing. Statistics derived from beat-to-beat fluctuations in heart rate or heart rate variability (HRV) have been used for this purpose, but the current predictability level is Low or moderate at best. OBJECTIVE The purpose of this study was to evaluate whether a recently proposed non-Gaussian index of HRV is a significant and independent mortality predictor in patients with congestive heart failure (CHF). METHODS Twenty-four-hour Hotter ECGs from 108 CHF patients were evaluated. Thirty-nine (36.1%) of the patients died during the follow-up period of 33 +/- 17 months. Cox proportional hazards regression analysis was performed to determine factors related to all-cause mortality. The factors evaluated derived from clinical information, including plasma brain natriuretic peptide, conventional time- and frequency-domain and fractal HRV measures, and a recently proposed non-Gaussian index X of HRV. RESULTS The short-term (< 40 beats) non-Gaussian index lambda(40) (hazard ratio per increment of unit standard deviation 1.64, 95% confidence interval [1.23, 2.18], P <.001) and the long-term (< 1,000 beats) index lambda(1000) (hazard ratio 1.42, 95% confidence interval [1.07, 2.18], P <.02), together with brain natriuretic peptide (hazard ratio 2.26, 95% confidence interval [1.45, 3.53], P <.001), are significant univariate risk predictors of mortality. In a multivariate model, lambda(40) (1.49, [1.13, 1.96], P <.005) and brain natriuretic peptide (2.39, [1.53, 3.75], P <.001) are independent predictors of the survival statistics of patients. None of the conventional HRV measures have predicted the mortality of patients in a significant and independent manner. CONCLUSION The results of this study indicate the usefulness of the short-term non-Gaussian index of HRV for risk prediction in patients with CHF.

A novel approach to momentary/instantaneous morphological assessment of phase histograms, extending phase statistics analysis, is used to investigate electrocardiograms during ventricular fibrillation (VF) in humans. By using empirical mode decomposition (EMD) and the Hilbert transform, we calculate the instantaneous phase of intrinsic mode functions (IMFs) in Holter data from 16 individuals, and construct the corresponding momentary phase histograms, enabling us to inspect the evolution of the waveform of the time series. A measure defined as the difference between the integrals of the probability distribution density of phase in different regions is then used to characterize the morphology of the momentary histograms and their temporal evolution. We find that the measure of morphology difference allows near perfect classification of the VF data into Survivor and non-survivor groups. The technique offers a new possibility to improve the effectiveness of intervention in defibrillation treatment and limit the negative side effects of unnecessary interventions. The approach can be implemented in real time and should provide a useful method for early evaluation of (fatal) VF.

It has been postulated that action potential duration (APD) is prolonged and I-Ks, a slow component of delayed rectifier potassium current, decreases in heart failure. We have reported that QT interval is prolonged and expression weight of KCNE1, coding I-Ks channel, increases in patients with heart failure. Since it is known that increase in KCNE1 increases the maximum conductance of I-Ks channel, the mechanism of APD prolongation is not explained by over expression of KCNE1. In this study, we construct a cardiac membrane action potential simulation model based on the experimental data from Xenopus oocytes expressed KCNQ1 and KCNE1 to investigate the relationship between increase in KCNE1 and APD. In addition, we investigated effect of reduction in Ca2+-independent transient outward potassium current (I-to) on APD in heart failure. In simulation, APD at 5ng KCNE1 was 180.96ms, which was 4.63% longer than that at 1ng KCNE1 (APD=172.96ms) and 55.9% longer than that at 0.2ng KCNE1 (APD=110.96ms). In the cases of KCNQ1 alone and 0.2ng KCNE1 coinjected, APD shortened as density of It. decreased, and APD prolonged as density of I-Ks decreased in other cases. This study shows that increase in KCNE1 expression level makes maximum conductance of I-Ks channel increase and I-Ks channel open slowly and conductance of I-Ks channel decrease according to the APD time scale. Therefore increasing the KCNE1 expression level may prolong APD with this mechanism. This method of constructing a simulation model based on experiments helps to explain the relationship between potassium currents and QT interval prolongation.

Autonomic nervous system plays a critical role in the regulation of cardiovascular system. We reviewed the autonomic nervous system examinations. Time and frequency domain analyses in heart rate variability is obtained from short- and long-term ECG and have predictive values of prognosis in various conditions of heart disease. Baroreflex testing evaluates autonomic modulation of arterial pressure. Baroreflex sensitivity is expressed by the(arterial blood pressure)/(RR interval in ECG) slope in response to infusion of nitroglycerine or phenylephrine. Decrease in baroreflex sensitivity is superior to heart rate variability in identifying patients with poor prognosis in post myocardial infarction. 123I-metaiodobenzylguanidine (MIBG) is an analogue of norepinephrine and hence cardiac 123I-MIBG imaging can visualize cardiac sympathetic nervous system. Defect area in the early phase(15 to 30 min after injection) indicates localization of ventricular denervation. MIBG uptake, measured as a heart to mediastinum activity ratio, had a high predictive vale for survival. Altered MIBG uptake may also play a significant role in the assessment of arrhythmogenic potential in patients with idiopathic ventricular fibrillation or congenital long QT syndrome.

Purpose: The purpose of this study was to determine the physiological responses of elderly women to a well-rounded exercise program performed in water (WEX). Methods: The participants (60-75 yr of age) were randomly divided into a training (TR) group (N = 15) and a control group (N = 15). The TR group participated in a 12-wk supervised WEX program, 70 min.day(-1), 3 d.wk(-1). The WEX consisted of 20 min of warm-up and stretching exercise, 10 min of resistance exercise, 30 min of endurance-type exercise (walking and dancing), and 10 min of cool-down exercise. Results: The WEX led to an increase (P < 0.05) in peak (V) over dot O-2 (12%) and (V) over dot O-2 at lactate threshold (20%). Muscular strength evaluated by a hydraulic resistance machine increased significantly at resistance dial setting 8 (slow) for knee extension (8%), knee flexion (13%), chest press (7%) and pull (11%), shoulder press (4%) and pull (6%), and back extension (6%). Vertical jump (9%), side-stepping agility (22%), trunk extension (11%), and FEV1.0 (7%) also increased significantly. There was a significant decrease in skin-fold thickness (-8%), low-density lipoprotein (LDL) cholesterol (-17%), and total cholesterol There were no significant changes in these variables in the control group. Conclusion: These results indicate that WEX elicits significant improvements in cardiorespiratory fitness, muscular strength, body fat, and total cholesterol in older adult women. Water-based exercise appears to be a very safe and beneficial mode of exercise that can be performed as part of a well-rounded exercise program.

Ion Channel Polymorphism and Cardiac Arrhythmia. Introduction: Congenital long QT syndrome (LQTS) is a genetically heterogeneous arrhythmogenic disorder caused by mutations in at least five different genes encoding cardiac ion channels. It was suggested recently that common polymorphisms of LQTS-associated genes might modify arrhythmia susceptibility in potential gene carriers. Methods and Results: We examined the known LQTS genes in 95 patients with definitive or suspected LQTS. Exon-specific polymerase chain reaction single-strand conformation polymorphism and direct sequence analyses identified six patients who carried only a single nucleotide polymorphism in KCNQ1 that is found in similar to 11% of the Japanese population. This 1727G>A substitution that changes the sense of its coding sequence from glycine to serine at position 643 (G643S) was mostly associated with a milder phenotype, often precipitated by hypokalemia and bradyarrhythmias. When heterologously examined by voltage-clamp experiments, the in vitro cellular phenotype caused by the single nucleotide polymorphism revealed that G643S-KCNQ1 forms functional homomultimeric channels, producing a significantly smaller current than that of the wild-type (WT) channels. Coexpression of WT-KCNQ1 and G643S-KCNQ1 with KCNE1 resulted in similar to 30% reduction in the slow delayed rectifier K+ current I-Ks without much alteration in the kinetic properties except its deactivation process, suggesting that the G643S substitution had a weaker dominant-negative effect on the heteromultimeric channel complexes. Conclusion: We demonstrate that a common polymorphism in the KCNQ1 potassium channel could be a molecular basis for mild I-Ks dysfunction that, in the presence of appropriate precipitating factors, might predispose potential gene carriers to life-threatening arrhythmias in a specific population.

Clinical usefulness of bone marrow transplantation (BMT) remains limited by myocardial damage during the post-transplantation period. Measurements of plasma atrial and brain natriuretic peptides (ANP, BNP) during the acute post-transplantation period could serve to monitor cardiac complications since these peptides are known to increase in heart failure depending on its severity. We prospectively analyzed ANP and BNP levels from 14 days before to 100 days after BMT in 46 consecutive patients undergoing allogeneic (n = 42) and autologous (n = 4) transplantation. Cardiac performance was assessed by echocardiography and radionuclide ventriculography. BNP and ANP levels of the patients on admission (baseline: day-14) were 16.3 +/- 13.3 pg/ml and 14.4 +/- 8.8 pg/ml, respectively. There were two different types of changes in the BNP and ANP levels. The 21 patients in group I showed dual peaks of elevation on day 1 (BNP = 164.4 +/- 136.0 pg/ml, P < 0.01; ANP = 44.5 +/- 35.4 pg/ml, NS) and day 14 (BNP = 233.9 +/- 106.2 pg/ml, P < 0.01; ANP = 142.7 +/- 154.6 pg/ml, P < 0.05), whereas the remaining 25 patients in group II had a single peak on day 1 (BNP = 124.5 +/- 124.9 pg/ml, P < 0.05; ANP = 45.2 42.4 pg/ml, NS). The left ventricular ejection fraction on day 63 was unchanged in both groups of patients from the baselines. The time to peak filling rate, a parameter of diastolic function in the radionuclide ventriculography, was significantly prolonged in group I patients (by 30 +/- 53%), whereas unaffected in group II patients. These results suggest that plasma BNP monitoring for 2 weeks after BMT may be useful for early detection of patients at high risk for cardiac dysfunction in the post-transplantation period.

不安定狭心症において胸痛に伴う著しいST低下やT変化を認める例は, その後急性心筋梗塞や心臓性突然死に移行する可能性が高い.しかしST部分やT波の変化は非特異的な場合も多く, 心筋虚血の検出における心電図の限界である.私たちは心筋梗塞発症前の不安定狭心症におけるST部分やT波に加えU波変化の出現誘導とその頻度について検討した.前壁梗塞へ進展した症例で有意に認められた主な所見は前壁誘導における0.1mV以上のST低下, 二相性T波, 陰性T波, 二相性U波, および陰性U波であった.一方, 下壁梗塞へ進展した症例では下壁誘導における二相性T波, T波終末部陰転, および二相性U波が有意所見であった.不安定狭心症より心筋梗塞へ移行した症例では特徴的な虚血性変化が認められていた.またこれらの虚血性変化の出現誘導によって梗塞部位の予知の可能性も示唆された.

Transplantation of cardiomyocytes into the heart is a potential treatment for replacing damaged cardiac muscle. To investigate the feasibility and efficiency of this technique, either a cardiac-derived cell line (HL-1 cells), or normal fetal or neonatal pig cardiomyocytes were grafted into a porcine model of myocardial infarction. The myocardial infarction was created by the placement of an embolization coil in the distal portion of the left anterior descending artery in Yorkshire pigs (n = 9), Four to 5 wk after creation of an infarct, the three preparations of cardiomyocytes were grafted, at 1 x 10(6) cells/20 mu L into normal and into the middle of the infarcted myocardium. The hearts were harvested and processed for histologic examinations 4 to 5 wk after the cell grafts. Histologic evaluation of the graft sites demonstrated that HL-1 cells and fetal pig cardiomyocytes formed stable grafts within the normal myocardium without any detrimental effect including arrhythmia, In addition, a marked increase in angiogenesis was observed both within the grafts and adjacent host myocardium. Electron microscopy studies demonstrated that fetal pig cardiomyocytes and the host myocardial cells were coupled with adherens-type junctions and gap junctions. Histologic examination of graft sites from infarct tissue failed to show the presence of grafted HL-I cells, fetal, or neonatal pig cardiomyocytes. Cardiomyocyte transplantation may provide the potential means for cell-mediated gene therapy for introduction of therapeutic molecules into the heart, (C) 1998 Elsevier Science Inc.

The contribution of inactivation of the L-type Ca2+ current (iCa) to overdrive suppression was investigated in rabbit sinoatrial (SA) node cells by use of the whole cell patch-clamp technique. In the current-clamp mode, rapid stimulation (6.7 Hz) for 30 s was followed by a transient increase in the cycle length of spontaneous action potentials of 135 +/- 52% (n = 3), i.e., "overdrive suppression." The iCa was measured in the voltage-clamp mode in the presence of 30 microM tetrodotoxin. An increase in the rate of depolarizing pulses (to 0 mV for 100 ms) from 1 to 6.7 Hz from a holding potential (HP) of -40 mV resulted in an abrupt, followed by a progressive, decrease in iCa; after 30 s of stimulation at 6.7 Hz, iCa was reduced to 15.5 +/- 1.8% (n = 4) of the control at 1 Hz. With an HP of -80 mV, a similar increase in the pulse rate caused much less reduction in iCa. When spontaneous action potentials were interrupted by a 30-s train of high-frequency voltage-clamp pulses (to 0 mV for 100 ms; 6.7 Hz) from an HP of -40 mV, there was again a marked decrease in iCa during the train, and after the train there was a transient suppression of spontaneous activity. In contrast, a similar interruption by high-frequency voltage-clamp pulses from an HP of -80 mV caused no decrease in iCa, and there was no suppression of spontaneous activity after the train. Neither delayed rectifier K+ current nor hyperpolarization-activated current was affected after a train of high-frequency voltage-clamp pulses. These findings suggest that overdrive suppression in the SA node is, in part at least, the result of a rate- and voltage-dependent inactivation of iCa.

To investigate the electrotonic modulation of sinoatrial (SA) node pacemaker activity by atrial muscle, single or multiple (2-7) SA node cells isolated from rabbit hearts were connected to a membrane model [resistance-capacitance (R-C) circuit] of an atrial cell through an external circuit that mimics the gap junctional conductance (G(c)) between cells. When G(c) was 0 nS (uncoupled conditions), all the preparations generated regular and stable spontaneous action potentials with a mean cycle length (SCL) of 263 +/- 45 ms (+/-SD, n = 35). Step increases of G(c) were associated with a progressive prolongation of SCL. At sufficiently high values of G(c), the spontaneous activity became irregular and finally stopped. We defined the threshold G(c) causing an appreciable SCL irregularity as the minimum G(c) at which the ratio of SD to mean of SCL was > 0.3. The threshold G(c) for a single SA node cell was calculated to be 0.58 nS. In the presence of acetylcholine (ACh; 0.05-0.2 mu M), the coupling-induced inhibition of spontaneous activity was greatly increased, and the threshold G(c) for a single SA node cell was decreased in a concentration-dependent manner. These findings show that the pacemaker activity of SA node cells is easily inhibited when the cells are coupled to a passive atrial cell model and the inhibition is amplified by ACh. Computer simulation using a modified Oxsoft HEART model indicates that the passive atrial cell model acts as a current sink, imposing a substantial outward current on the SA node cell, and ACh amplifies the effect by activating an additional outward current.

To investigate the electrotonic modulation of sinoatrial (SA) node pacemaker activity by atrial muscle, single or multiple (2-7) SA node cells isolated from rabbit hearts were connected to a membrane model [resistance-capacitance (R-C) circuit] of an atrial cell through an external circuit that mimics the gap junctional conductance (Gc) between cells. When Gc was 0 nS (uncoupled conditions), all the preparations generated regular and stable spontaneous action potentials with a mean cycle length (SCL) of 263 +/- 45 ms (+/- SD, n = 35). Step increases of Gc were associated with a progressive prolongation of SCL. At sufficiently high values of Gc, the spontaneous activity became irregular and finally stopped. We defined the threshold Gc causing an appreciable SCL irregularity as the minimum Gc at which the ratio of SD to mean of SCL was > 0.3. The threshold Gc for a single SA node cell was calculated to be 0.58 nS. In the presence of acetylcholine (ACh; 0.05-0.2 microM), the coupling-induced inhibition of spontaneous activity was greatly increased, and the threshold Gc for a single SA node cell was decreased in a concentration-dependent manner. These findings show that the pacemaker activity of SA node cells is easily inhibited when the cells are coupled to a passive atrial cell model and the inhibition is amplified by ACh. Computer simulation using a modified Oxsoft HEART model indicates that the passive atrial cell model acts as a current sink, imposing a substantial outward current on the SA node cell, and ACh amplifies the effect by activating an additional outward current.

We examined the electrotonic effects of atrial muscle on the pacemaker activity in the sinoatrial (SA) node. Isolated rabbit SA node cells were coupled to a membrane model of a single atrial cell via an external circuit which mimics the gap junctional connection between cells. Step increases of the coupling conductance (Gc) induced a progressive prolongation of spontaneous cycle length (SCL) associated with characteristic changes in the action potential configuration. At Gc above a certain level, the spontaneous activity became irregular and finally stopped. We defined the ''threshold Gc'' as the Gc at which the SCL irregularity (SD/mean) was greater than 0.3. The threshold Gc for a single SA node cell wth a mean capacitance of 28 pF, was 0.58 +/- 0.04 nS (mean +/- SEM, n = 16). In the presence of acetylcholine (ACh) 0.05-0.2 mu M, the coupling-induced inhibition of spontaneous activity was enhanced and the threshold Gc was decreased in a concentration-dependent manner (0.14 +/- 0.03 nS at 0.1 mu M ACh). These findings suggest that the regular pacemaker activity of a single SA node cell is easily inhibited when it is coupled directly to an atrial cell, and that ACh enhances the coupling-induced inhibition of spontaneous activity.

Electrotonic interaction between the sinoatrial (SA) node and surrounding atrial muscle was investigated in a computer simulation using a modified Oxsoft HEART model (Oxsoft, Oxford, UK). When an SA node cell model was coupled to a passive atrial membrane model (RC circuit) with various coupling conductances (G(c)), there was a G(c)-dependent prolongation of spontaneous cycle length (SCL). At a sufficiently high value of G(c), the spontaneous activity was finally stopped. A nonlinear relationship between G(c) and SCL was obtained, similar to that observed in experiments on rabbit SA node cells. When the muscarinic potassium current (i(K,ACh)) was activated in the SA node cell model, the coupling-induced inhibition of pacemaker activity was potentiated. Although coupling current and i(K,ACh) were additive, their effects on SCL were more than additive because of the nonlinear dependence of SCL on net current. A decrease in the input resistance of the atrial membrane model to simulate the activation of i(K,ACh) in atrial muscle was also shown to potentiate the coupling-induced inhibition of SA node spontaneous activity.