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BACKGROUND Sleep-disordered breathing (SDB) is highly associated with arterial hypertension (HT). Sympathetic hypertonia increases the risk of sudden cardiac death in patients with sleep apnea. This study aims to noninvasively investigate the electrophysiological features in SDB patients with and without arterial HT. METHODS Fifty-three patients with SDB were classified into two groups: SDB group and SDB + HT group. Twenty subjects with arterial HT were enrolled as controls (HT group). To assess arrhythmogenic vulnerability, high-resolution 24-hour ambulatory electrocardiograms were obtained for analyzing continuous late potential (LP), T-wave amplitude variability (TAV), and heart rate variability (HRV). RESULTS A higher incidence of positive LP was observed in the SDB + HT (85%) group than that observed in the SDB (50%) and HT (20%) groups (P < 0.01). TAV was highest in the SDB + HT group (78 μV) compared with the SDB (61 μV) and HT groups (42 μV; P < 0.01). Positive LP and TAV values were observed at night in the SDB + HT and SDB groups. The low-frequency/high-frequency of the HRV analysis was highest in the SDB + HT (4.7) group compared with that in the SDB (2.9) and HT (2.9) groups (P = 0.01). CONCLUSION Nocturnal LP, TAV, and HRV examinations were useful to investigate arrhythmogenesis. SDB patients with arterial HT showed a high prevalence of depolarization and repolarization abnormalities and relative sympathetic hyperactivity. This suggests that an electrophysiological instability is more prevalent in SDB patients with arterial HT.

Spontaneous coronary artery dissection (SCAD) is an uncommon etiology of Acute Coronary Syndrome (ACS); however, appropriate treatment based on early diagnosis can improve outcomes. We screened medical records of all ACS patients who were admitted to one of 8 different centers (Cardiovascular Research Consortium-8 Universities) and underwent emergent coronary angiography from January 2001 to December 2014. From these ACS patients, we selected the patients with SCAD based on a review of the results of coronary angiography. Patient demographics, treatment, and in-hospital and long-term outcomes were determined from a review of medical records and angiographic findings. Of the 9377 ACS patients, 20 (0.21%) were diagnosed with SCAD. In these 20 SCAD patients, the mean age was 48.6 ± 12.0 years old, and 19 patients were female (95.0%). In 3 patients (15%), SCAD was associated with pregnancy. Coronary spasm was associated with SCAD in 2 patients (10%). Two patients (10%) were treated conservatively, and percutaneous coronary intervention was performed in 18 patients (90%). Two patients (10.0%) received target lesion revascularization, and one patient (5%) received coronary artery bypass grafting (CABG). SCAD recurred in one patient (5%), and there was in-hospital death in one patient (5%) after CABG. The patient demographics and outcomes in this study were compatible with recent reports of SCAD, except for the trigger of coronary spasm. SCAD should be suspected in middle-aged female ACS patients, and conservative treatment is recommended when there is no ongoing ischemia or left main trunk dissection. In addition, close follow-up is important.

It has been known that heart disease—such as myocardial infarction (MI), cardiac hypertrophy, or heart failure—alters the molecular structure and function of the gap junction, which can lead to an abnormal heart rhythm. Radiation has been shown to modulate intercellular communication in the skin and lungs by increasing connexin43 (Cx43) expression. Understanding how Cx43 upregulation is induced in a diseased heart can help provide a new perspective to radiation therapy for arrhythmias. In a recent study with rabbits after MI, carbon ions were accelerated to 290 MeV/u and extracted in the air; a biologically (cell kill) uniform 6-cm spread-out Bragg peak beam was generated, and beam tissue depth was set to 30 mm with energy degraders to the depth position. Targeted heavy ion irradiation (THIR) with 15 Gy to the left ventricle increased Cx43 expression, improved conductivity, decreased the spatial heterogeneity of repolarization, and reduced the vulnerability of rabbit hearts to ventricular arrhythmias after MI. In clinically normal rabbits, THIR > = 10 Gy caused a significant dose-dependent increase of Cx43 protein and messenger RNA 2 weeks after irradiation. The left (irradiated) and right (nonirradiated) ventricles exhibited circumferential upregulation of Cx43 lasting for at least 1 year. There were no significant changes in electrocardiograms and echocardiograms, indicating no apparent injury for 1 year. A single exposure of 135 MeV/u THIR with 15 Gy to a dog heart attenuated vulnerability to ventricular arrhythmia after the induction of MI for at least 1 year through the modulation of Cx43 expression. This long-lasting remodeling effect on gap junctions may lay the groundwork to novel therapies against life-threatening ventricular arrhythmias in structural heart disease. To date, there have been few investigations into the effects of carbon-ion irradiation on electrophysiological properties in the human heart. Patients with mediastinum cancer were investigated for 5 years after treatment that included irradiation to the heart, and investigators found that carbon-ion beam irradiation to the heart is not immediately cardiotoxic and demonstrates consistent signals of arrhythmia reduction. Its practical application in non–cancer treatment, such as in arrhythmia treatment, is highly anticipated.

BACKGROUND Macitentan is a novel, dual endothelin receptor antagonist with sustained receptor binding, used for the long-term treatment of pulmonary arterial hypertension (PAH). In the present study, we assessed the efficacy and safety of macitentan in Japanese patients with PAH. METHODS AND RESULTS Macitentan was administered at a once-daily dose of 10 mg in 30 patients. The primary endpoint was change in pulmonary vascular resistance (PVR) from baseline to week 24. Change to week 24 in the other hemodynamic parameters, 6-min walk distance (6MWD), World Health Organization (WHO) functional class, and plasmaN-terminal pro-brain natriuretic peptide (NT-pro-BNP), as well as time to clinical deterioration up to week 52 were also assessed as secondary endpoints. In the 28 patients on per-protocol analysis, PVR decreased from 667±293 to 417±214 dyn·sec·cm(-5)(P

BACKGROUND Selexipag is an orally available prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. In this open-label Phase II trial, the efficacy and safety of selexipag in Japanese patients with pulmonary arterial hypertension (PAH) is examined.Methods and Results:Selexipag was administered at 200 μg twice daily and titrated up to 1,600 μg by increments of 200 μg in 37 subjects to reach the individual maximum tolerated dose. At 16 weeks, in 33 patients comprising the per-protocol set, the pulmonary vascular resistance (PVR; primary endpoint) decreased from 683.2±237.3 to 560.3±238.7 dyn·s/cm5(P

Background High-risk patients with Brugada syndrome (BrS) have inherent late potential (LP) fluctuations that might be explained by autonomic activity, electrolyte abnormality, and body temperature changes. However, the correlation between postural changes and LP determinates remains unknown. Methods Forty patients with BrS (38 men, 43.9 ± 13.5 years) and 15 controls (15 men, 42.4 ± 11.2 years) were enrolled. LP variations were investigated at five body positions using high-resolution ambulatory monitoring electrocardiography (HR-ambulatory ECG). The HR-ambulatory ECG was recorded for 3 hours and LP parameters (fQRSd, LAS40, and RMS40) were obtained for at least 15 minutes in each at the supine, left and right lateral decubitus, and prone and sitting positions. Results Determinate LP in the BrS group was significantly abnormal in all positions. Among the five body positions, positive LP were much more frequent in the supine and left and right lateral decubitus positions than in the prone and sitting positions and normalized in the last two positions in patients with BrS. RMS40 variance by postural change was significantly larger in the coved group than in the saddle back group. Determinate LP improved in the sitting position compared to the supine position in the coved group. Conclusions Positive LP findings normalized in the sitting position in patients in the coved BrS group with a resuscitation history, suggesting that depolarization instability might be related to the risk of fatal ventricular arrhythmia. Posture-induced LP variance should be examined using HR-ambulatory ECG analysis in patients with BrS.

Background The impact of regional wall motion abnormality (RWMA) on the accuracy of heart failure with preserved ejection fraction (HFpEF) diagnosis using the E/e′ ratio, which is a non-invasive parameter of left ventricular diastolic performance, is unknown. The purpose of this study was to elucidate the impact of RWMA of the lateral wall (RWMAlat) on the correlation between E/e′ and invasive parameters of left ventricular diastolic performance. Methods Three hundred and eight consecutive patients undergoing tissue Doppler imaging and catheterization pressure examination were retrospectively analyzed. E/e′ was calculated as the ratio of early diastolic transmitral flow velocity to mitral annular velocity at the lateral wall. Invasive parameters including left ventricular end-diastolic pressure (LVEDP) and isovolumetric relaxation time constant (τ) were assessed based on the left ventricular pressure study. Correlation coefficients between E/e′ and these invasive parameters were analyzed and compared between cases with RWMAlat and without RWMA. Results LVEDP and τ correlated well with E/e′ for all 308 patients (r = 0.51 and r = 0.65, respectively). Sixty-two patients had RWMA; the remaining 246 did not have RWMAlat. We confirmed that the presence of RWMAlat weakens both the correlations between E/e′ and LVEDP (r = 0.574 vs. r = 0.381), and E/e′ and τ (r = 0.729 vs. r = 0.461). Conclusions Although E/e′ correlates well with parameters of left ventricular diastolic performance assessed by invasive methods, the presence of RWMAlat worsens this correlation. In cases with RWMAlat, careful assessment is required for HFpEF diagnosis because the diagnostic value of the E/e′ ratio could be decreased compared to patients without RWMAlat.

Iodine-123 metaiodobenzylguanidine (Twenty New Zealand white rabbits treated with phenol or sham were prepared under anesthesia. Sympathetic innervation was quantified using autoradiography and immunostaining 4 weeks after phenol application, and electrophysiological study was performed.The presence of hyperinnervation in the nondenervated regions of denervated rabbit hearts suggests that heterogeneous neural remodeling occurs in regions with seemingly normal

Background The therapeutic goals of atrial fibrillation (AF) patients are to reduce symptoms and prevent severe complications associated with AF. This study compared the efficacy of flecainide versus pilsicainide in reducing the frequency of AF and improving quality of life (QOL) in symptomatic paroxysmal AF patients without structural heart disease. Methods The Atrial Fibrillation and Quality Of Life (AF-QOL) study was a prospective, multicenter, randomized, open-label crossover study that compared flecainide and pilsicainide as antiarrhythmic drug therapy. Patients were randomized to receive 3 months of treatment with flecainide twice daily or pilsicainide 3 times daily. Each treatment consisted of a dose-finding phase (weeks 1–4) and an efficacy phase (weeks 5–12). Forty-three patients completed the trial. The main outcome was the number of days with documented AF episodes using a patient-operated electrocardiogram. QOL questionnaires (SF-36 and AF-specific QOL scores) were also completed. Results The median (range) AF frequencies (days/8 weeks) were 2 (0–50) in the flecainide treatment group and 1 (0–54) in the pilsicainide treatment group (no significant between-group difference). No significant difference in the first recurrence of AF during the efficacy phase was noted between flecainide and pilsicainide treatments. The frequency and severity scores of AF-related symptoms improved from baseline to the end of the treatment periods. No significant differences in SF-36 or AF-related QOL scores were noted between the treatment groups. Conclusions This study found no difference in AF frequency or QOL between symptomatic paroxysmal AF patients who received flecainide or pilsicainide.

Targeted external heavy ion irradiation (THIR) of rabbit hearts 2 weeks after myocardial infarction (MI) reduced the vulnerability of fatal ventricular tachyarrhythmias (VT/VF) in association with the increased connexin43 (Cx43). Increased Cx43 was maintained for at least 1 year in normal rabbits, but the long-term antiarrhythmic effects in the MI model are unknown. We investigated the propensity for late potentials and VT/VF inducibility.Intracoronary injection of microspheres was performed to induce nontransmural MI in anesthetized eight beagles. Four beagles were treated with THIR (Filtered QRS duration was exacerbated after MI and remained unchanged for 1 year in the MI group (118 ± 1.4 ms), but significantly returned toward baseline in the MI + THIR group (109 ± 6.9 ms). Similarly, root mean square voltage of the last 40 ms was exacerbated after MI, but recovered after THIR. VT/VF inducibility decreased to 25% in the MI + THIR group compared with 100% in the MI group. Immunostaining Cx43 expression in cardiac tissues significantly increased by 24-45% in the MI + THIR group. Left ventricular ejection fractions remained within the normal range in both groups.A single exposure of the dog heart to

Pulmonary vein isolation (PVI) with radio-frequency catheter ablation (RFCA) is effective therapy for the patients with paroxysmal atrial fibrillation (pAF). However, it is not easy to predict relapse of pAF. Approximately 70% pAF patients were maintained sinus rhythm for 1 year after PVI in Japan. In this study, all of the cases were underwent chest computed tomography (CT) to check for the morphology and positional relationship of the left atrium. We detected relapse cases that exhibited spur formation in the thoracic vertebrae. Therefore, we conducted an investigation based on the hypothesis that, "Because hyperostosis involves proliferative changes in the synovium or pia mater cells with an inflammatory basis, it is related to the onset of atrial fibrillation." The study sample consisted of 24 sequential cases (males: 20, mean age: 66.2 ± 6.9 years) of drug-resistant pAF that underwent PVI at our hospital between January and May, 2015. When subjects were divided into a relapse group and a non-relapse group and 21 background factors were compared, it was found that the relapse group subjects were older than the non-relapse group subjects (70.3 ± 7.2 vs 64.1 ± 5.7, p = 0.04). The proportion of cases with thoracic vertebra hyperplasia was markedly high in the relapse group (6 cases [75%] vs. 3 cases [18%], p = 0.007). No statistically significant differences were observed between the two groups for any other background factors. Our results suggested that thoracic vertebra hyperplasia could be a marker for predicting relapse after PVI in pAF patients.

The aim of this study was to investigate the significance of late potential (LP) after percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS).We enrolled 135 consecutive patients with ACS admitted to Tokai University Hospital from February to December 2012. Twenty-four hour high-resolution ambulatory electrocardiogram was performed between post-PCI procedure and hospital discharge. The patients were divided into the LP-positive (33 patients) and LP-negative (102 patients) groups, and the relationship between LP and re-hospitalization was prospectively investigated.The body mass index, serum creatinine, and creatine phosphokinase-MB were higher in the LP-positive group than in the LP-negative group (p0.05). The re-hospitalization rate was higher in the LP-positive group. (9 patients, 27.3% vs. 10 patients, 9.8%; p = 0.03). There were no significant differences in the occurrence of ventricular tachycardia or cardiac death between the groups. According to Kaplan-Maier analysis, proportion of re-hospitalization was significantly lower in the LP-positive group than in the LP-negative group (p = 0.01; average follow-up, 451.4 ± 25.9 days). The odds ratio of LP presence was 3.45 (highest among all variables; 95% confidence interval, 1.3-9.4; p0.01).Positive LP in patients with ACS after PCI may predict re-hospitalization.

Background: The 12-lead electrocardiogram (ECG) has relatively poor specificity for identifying acute pulmonary embolism (APE). The aim of this study was to investigate ECG abnormalities according to 2 different criteria and their usefulness for assessing changes in APE. Methods and Results: Fifty-two APE patients underwent ECG examinations in the acute and chronic phases. ECG abnormalities were assessed according to Stein's criteria (QRS complex abnormalities and T wave inversion in any lead except aVL, III, aVR, or V1) and Kosuge's criteria (T wave inversion in any lead except aVR or aVL). Many patients had electrocardiographic abnormalities in the acute phase, but no specific abnormalities were found. According to Kosuge's criteria, the frequency of T wave inversion was higher than that of abnormal QRS complexes and T wave inversion according to Stein's criteria (P

Heart injury due to electric shock is currently diagnosed based on electrocardiogram (ECG) changes or elevated levels of myocardial enzymes or both. However, the rate at which ECG detects abnormalities is very low; thus, the estimated rate of the diagnosis of myocardial damage due to electric shock is lower than the actual rate. The method of nuclear medicine study of the heart is superior with regard to evaluating transient ischemia, such as angina pectoris, in patients whose ECG and myocardial enzyme levels are normal. Therefore, we attempted to diagnose transient myocardial damage in electric shock patients by using nuclear medicine study of the heart.

Sleep-disordered breathing (SDB) is highly associated with arterial hypertension (HT). Sympathetic hypertonia increases the risk of sudden cardiac death in patients with sleep apnea. This study aims to noninvasively investigate the electrophysiological features in SDB patients with and without arterial HT.Fifty-three patients with SDB were classified into two groups: SDB group and SDB + HT group. Twenty subjects with arterial HT were enrolled as controls (HT group). To assess arrhythmogenic vulnerability, high-resolution 24-hour ambulatory electrocardiograms were obtained for analyzing continuous late potential (LP), T-wave amplitude variability (TAV), and heart rate variability (HRV).A higher incidence of positive LP was observed in the SDB + HT (85%) group than that observed in the SDB (50%) and HT (20%) groups (P0.01). TAV was highest in the SDB + HT group (78 μV) compared with the SDB (61 μV) and HT groups (42 μV; P0.01). Positive LP and TAV values were observed at night in the SDB + HT and SDB groups. The low-frequency/high-frequency of the HRV analysis was highest in the SDB + HT (4.7) group compared with that in the SDB (2.9) and HT (2.9) groups (P = 0.01).Nocturnal LP, TAV, and HRV examinations were useful to investigate arrhythmogenesis. SDB patients with arterial HT showed a high prevalence of depolarization and repolarization abnormalities and relative sympathetic hyperactivity. This suggests that an electrophysiological instability is more prevalent in SDB patients with arterial HT.

Radiation has been shown to enhance intercellular communication in the skin and lungs through an increase of connexin43 (Cx43) expression. If analogous Cx43 up-regulation is induced in the diseased heart, it would provide a new perspective in radiation therapy for arrhythmias. The aim of the present study is to test this hypothesis.Non-transmural myocardial infarction (MI) was created in 24 rabbits by microsphere injection into the coronary arteries. Twenty-four rabbits without MI were used as controls. Targeted external heavy ion beam irradiation (THIR; 15 Gy) was applied 2 weeks after MI with an accelerator (HIMAC, Chiba, Japan).The THIR was associated with an increase of Cx43 mRNA and protein levels in the left ventricle in control as well as in MI rabbits. THIR also increased lateralization of Cx43, which was no longer colocalized with cadherins. In MI hearts, immunoreactive Cx43 signals were reduced in the peri-infarct zone, and the reduction was reversed by THIR. In-vivo epicardial potential mapping on the free wall (64 unipolar electrodes to cover 7 x 7 mm) in MI hearts revealed reduced conduction velocity, whereas dispersion of the activation-recovery interval (ARI) was increased compared with controls, and these changes were reversed by THIR. The vulnerability for ventricular tachyarrhythmias (VT/VF), which was estimated by programmed stimulation, was increased in MI hearts, and this increased vulnerability to arrhythmias was reversed by THIR.THIR increases Cx43 expression, improves the conductivity, decreases the spatial heterogeneity of repolarization, and reduces the vulnerability of rabbit hearts to ventricular arrhythmias after MI. THIR could have an antiarrhythmic potential through an improvement of electrical coupling.

Background Because nifekalant hydrochloride (NIF) displayed a superior defibrillating effect on ventricular tachycardia/fibrillation (VT/VF) in cardiopulmonary arrest (CPA) patients, despite some QT prolongation, its effect on transmural dispersion of repolarization (TDR) in the left ventricle (LV) in an animal model of CPA was investigated. Methods and Results Eight beagle dogs were created with a myocardial infarction under anesthesia, and then VT/VF induction by continuous stimulation and cardiopulmonary resuscitation (CPR) were repeated. NIF (0.3 mg/kg) was administered under acidotic conditions (pH 7.26). The QTc interval measured by Y-lead ECG showed no significant prolongation before and after NIF. The activation recovery interval (ARI) measured by 64-lead LV surface mapping showed minimum ARI prolongation (40%) by NIF without maximum ARI prolongation, and as a result the ARI dispersion decreased by 67%. The repolarization time (RPT) with the plunge electrode showed 13-19% prolongation in the subendocardium and subepicardium with CPR, but NIF prolonged the RPT in the middle layer alone (17%), and as a result Plunge-TDR decreased by 82% (n=8, p

Background Spiral re-entry plays the principal role in the genesis of ventricular tachycardia and ventricular fibrillation (VT/VF). The specific IKr blocker, nifekakant (NIF) has, often in combination with lidocaine (LID), recently been used in Japan to prevent recurrent VT/VF, but the combined effects of these drugs on spiral re-entry had never been investigated. Methods and Results A ventricular epicardial sheet was obtained from 13 Langendorff-perfused rabbit hearts by means of a cryoprocedure, and epicardial excitations were analyzed with a high-resolution optical mapping system. Nifekakant (0.5 μmol/L) caused significant prolongation of action potential duration (APD) and LID (3 μmol/L) attenuated the APD prolongation without affecting the conduction velocity. VT were induced in 6 hearts by cross-field stimulation, and single- or double-loop spirals circulating around variable functional block lines were visualized during the VT. Nifekakant reduced VT cycle length and caused early termination in association with destabilization of the spiral dynamics (prolongation of functional block line, frequent local conduction block, and extensive meandering). These modifications of spiral-type re-entrant VT by NIF were prevented by addition of LID. Conclusions The effects of NIF on the spiral excitations are reversed by LID. This interaction should be taken into account when these drugs are used in combination to treat VT/VF. (Circ J 2005; 69: 576 - 584)

BACKGROUND: High‐risk patients with Brugada syndrome (BrS) have inherent late potential (LP) fluctuations that might be explained by autonomic activity, electrolyte abnormality, and body temperature changes. However, the correlation between postural changes and LP determinates remains unknown. METHODS: Forty patients with BrS (38 men, 43.9 ± 13.5 years) and 15 controls (15 men, 42.4 ± 11.2 years) were enrolled. LP variations were investigated at five body positions using high‐resolution ambulatory monitoring electrocardiography (HR‐ambulatory ECG). The HR‐ambulatory ECG was recorded for 3 hours and LP parameters (fQRSd, LAS40, and RMS40) were obtained for at least 15 minutes in each at the supine, left and right lateral decubitus, and prone and sitting positions. RESULTS: Determinate LP in the BrS group was significantly abnormal in all positions. Among the five body positions, positive LP were much more frequent in the supine and left and right lateral decubitus positions than in the prone and sitting positions and normalized in the last two positions in patients with BrS. RMS40 variance by postural change was significantly larger in the coved group than in the saddle back group. Determinate LP improved in the sitting position compared to the supine position in the coved group. CONCLUSIONS: Positive LP findings normalized in the sitting position in patients in the coved BrS group with a resuscitation history, suggesting that depolarization instability might be related to the risk of fatal ventricular arrhythmia. Posture‐induced LP variance should be examined using HR‐ambulatory ECG analysis in patients with BrS.

An estimated 50,000 patients have heart failure (HF) in Japan, and the left ventricular ejection fraction (LVEF) is the typical predictor of prognosis. The identification of a noninvasive marker to predict most high-risk patients is urgently needed. This study aimed to log the continuous ventricular late potential (LP) by using high-resolution ambulatory monitoring in patients with HF with non-sustained ventricular tachycardia, and determine the association between the LP variation and prognosis.The 90 hospitalized patients were classified into cardiogenic death (n = 10) and non-death (n = 80) groups. The LVEF, LP, and coefficient of variation (CV) of the filtered QRS (fQRS), and low-amplitude signal40 µV for the terminal QRS portion of (LAS40) of both groups were evaluated. The maximum fQRS over 24 h was defined as the maximum fQRS (Max-fQRS).The results were as follows: (1) cardiogenic death occurred in 32% (10/31 patients) with an LVEF ≤ 45% and a Max-fQRS ≤ 114 ms; (2) cardiogenic death occurred in 38% (10/26 patients) with a LAS40-CV ≥ 0.09; and (3) using LVEF, Max-fQRS, and LAS40-CV as the three predictors, the specificity and accuracy were 83% and 82%, respectively, with an odds ratio of 12.3.LAS40 variations and increases might be new risk indicators of prognosis.

Background —Heterogeneity of sympathetic innervation is thought to contribute to the potential for fatal arrhythmia. However, little is known about the effects of heterogeneous innervation on repolarization. Methods and Results —To assess this relationship, we measured activation recovery intervals (ARIs) from 64 epicardial sites in 11 rabbits studied 2 weeks after regional denervation produced by phenol and 4 sham-operated rabbits. ARI results were compared with the distribution of sympathetic innervation measured from 3D reconstructions of serial autoradiographs of [ 125 I]metaiodobenzylguanidine and 99m Tc-sestamibi. ARIs were recorded during baseline sinus rhythm, norepinephrine (NE) infusion (0.1 μg · kg −1 · min −1 ), and left stellate ganglion stimulation (SS). NE shortened ARI in 98% of electrodes in the denervated region. The degree of ARI shortening and dispersion increased ( P P P Conclusions —The magnitude and dispersion of local repolarization responses are related to the severity of denervation, as well as the type of stimulation: neural (SS) versus humoral (NE). The differences may relate to the concentration of NE released.

The purpose of the study was to determine whether a new KATP channel opener, Y 26763 (Y), can influence the electrophysiological properties in the ischemic myocardium as well as to determine whether the blunting effect of the alpha 1-adrenoceptor antagonist bunazosin (BN) on an ischemia-induced shortening of repolarization time can be related to the KATP channel activity. The anterior descending branch of the left coronary artery was ligated four times for 5 minutes, separated by 15 minutes of reperfusion (stages 1-4) to test the dose-dependent effect of drugs on repolarization. Dogs received either vehicle (n = 9), Y (0.4, 2.0, and 4.0 micrograms/kg at stages 2, 3, and 4, respectively, with 0.4 microgram/kg/min drip infusion at each of stages 2-4, n = 7), BN (0.1 mg at each of stages 2-4, n = 8), or a combination of these two drugs (BN + Y, the same dose of BN and Y in groups BN and Y, respectively, n = 9). Drugs were administered into the left atrium. The monophasic action potential (MAP) and regional electrograms were recorded. The MAP90 and the duration of the slow deflections (DSD) of the regional electrogram were used as markers of repolarization. The Vmax of the MAP and the rapid deflections (DRD) of the regional electrogram were used as markers of conduction. Y augmented an ischemia-induced shortening of MAP90 and DSD in proportion to an increase in the dose given and the plasma concentration (P < .05-.01), especially at the epicardial site. BN and BN + Y blunted the ischemia-related shortening of MAP90 and DSD, causing a reduction in repolarization time dispersion between the ischemic and normal zones. There were no significant changes in the Vmax or DRD in the ischemic zone between periods before and after an increase in each drug dose in the four groups. None of the seven dogs developed ventricular tachycardia (VT)/ventricular fibrillation (VF) in the Y group, whereas two of the eight dogs in the BN group, three of the nine dogs in the BN + Y group, and three of the nine dogs in the control group developed VT/VF. These results suggest that the alpha 1-adrenergic blocker bunazosin blunts the shortening effect of KATP channel activator on repolarization time, and that the KATP channel opener Y may be antiarrhythmic, although the repolarization time dispersion during myocardial ischemia is increased.

Background: There are few reports on long-term convalescence with regard to cardiac injury caused by blunt chest trauma. Nuclear medicine study of the heart (NMSH) in the early stages of injury is reportedly superior to detect the correlation between injury and fatal arrhythmia. Therefore, we prospectively performed NMSH and Holter electrocardiogram (ECG) in the early and chronic stages for a cardiac injury patient, and we longitudinally examined the recovery process and the occurrence of fatal arrhythmia. Methods and Results: A total of 202 patients with blunt chest trauma were admitted to our hospital between April 2006 and January 2007. Of 65 patients who were diagnosed with cardiac injury by ECG, a myocardial enzyme, or cardiac ultrasonography, 11 were enrolled in this study because they agreed to outpatient visiting for regular examinations for 1 year. NMSH showed positive findings in 6 of the 11 patients in the acute period of < 1 month. Twelve months later, five patients improved but still exhibited protracted cardiac damage without complete recovery. Among the six patients in whom NMSH showed positive findings, Holter ECG indicated an abnormal finding in two patients in the acute period and in four patients in the chronic period, and detected one patient with a nonsustained ventricular tachycardia in the chronic period. Conclusion: Cardiac injuries may exacerbate cardiac functions and lead to fatal arrhythmia during the chronic period. Therefore, evaluating recovery for at least 12 months after myocardial damage is necessary to prevent sudden cardiac death.

To evaluate the switching from an angiotensin receptor blocker (ARB) to a drug combination containing an ARB and a diuretic drug in terms of effects on hypertension, cardiac load, and cardiac function.In a study conducted on 82 patients with a history of heart failure and hypertension who had been treated with an ARB but failed to reach the target blood pressure, ongoing oral ARB treatment was switched to a drug combination of losartan and hydrochlorothiazide (HCTZ). Using ambulatory blood pressure monitoring (ABPM), the variations in blood pressure and the effects on cardiac load and cardiac function were evaluated before and after treatment.Comparison of the ABPM findings before and after switching treatment showed significant improvements in mean systolic and diastolic blood pressure, improvements in systolic and diastolic blood pressure 1 hour before getting out of bed, and improvements in the plasma levels of human brain natriuretic peptide as an indicator of cardiac load.The drug combination of losartan and hydrochlorothiazide showed a stronger antihypertensive effect than that of the conventional ARB and improved heart function.

Risk stratification is important in the management of Brugada syndrome (BrS). Late potentials (LPs) and T-wave amplitude variability (TAV) in high-resolution ambulatory electrocardiography (ECG) were retrospectively investigated.One hundred and twenty-seven patients diagnosed with BrS on 12-lead ECG were classified into 3 groups: documented ventricular fibrillation (VF)/asystole (n=19), episodes of syncope alone (n=30), and asymptomatic (n=78). Healthy volunteers were enrolled as controls (n=25). In the BrS patients, LPs showed appreciable circadian periodicity; filtered QRS duration (fQRS) and duration of the terminal low-amplitude signal40 μV (LAS40) increased, whereas root mean square voltage of the terminal 40 ms of the fQRS (RMS40) decreased at night compared with the day. TAV did not have such a circadian periodicity. LP-positive incidence (night-time) and peak TAV were as follows: VF/asystolesyncope/asymptomaticcontrol (P0.001). VF/asystole was discriminated from control at a ratio of 81-84% by night-time LPs (fQRS116 ms, LAS4035 ms, RMS4025 μV) or peak TAV (54 μV); VF/asystole was discriminated from syncope/asymptomatic at a ratio of 60-69%, by night-time LPs (fQRS122 ms, LAS4042 ms, RMS4018μV) or peak TAV (58 μV). Combined analysis of LPs and peak TAV increased the discriminant ratio up to 93% and 77%, respectively.Analysis of both LPs and TAV (taking circadian periodicity into account) is useful in identification of high-risk BrS patients.

A previous study from our laboratory has shown that a single targeted heavy ion irradiation (THIR; 15 Gy) to rabbit hearts increases connexin43 (Cx43) expression for 2 wk in association with an improvement of conduction, a decrease of the spatial inhomogeneity of repolarization, and a reduction of vulnerability to ventricular arrhythmias after myocardial infarction. This study investigated the time- and dose-dependent effects of THIR (5–15 Gy) on Cx43 expression in normal rabbit hearts ( n = 45). Five rabbits without THIR were used as controls. A significant upregulation of Cx43 protein and mRNA in the ventricular myocardium was recognized by immunohistochemistry, Western blotting, and real-time PCR from 2 wk up to 1 yr after a single THIR at 15 Gy. THIR ≥10 Gy caused a significant dose-dependent increase of Cx43 protein and mRNA 2 wk after THIR. Anterior, lateral, and posterior free wall of the left ventricle, interventricular septum, and right ventricular free wall were affected similarly by THIR in terms of Cx43 upregulation. The radiation-induced increase of immunolabeled Cx43 was observed not only at the intercalated disk region but also at the lateral surface of ventricular myocytes. The increase of immunoreactive Cx43 protein was predominant in the membrane fraction insoluble in Triton X-100, that is the Cx43 in the sarcolemma. In vivo examinations of the rabbits 1 yr after THIR (15 Gy) revealed no significant changes in ECGs and echocardiograms (left ventricular dimensions, contractility, and diastolic function), indicating no apparent late radiation injury. A single application of THIR causes upregulation and altered cellular distribution of Cx43 in the ventricles lasting for at least 1 yr. This long-lasting remodeling effect on gap junctions may open the pathway to novel therapy against life threatening ventricular arrhythmias in structural heart disease.

Background: In Japan, intravenous nifekalant ( NIF) was often used for direct current cardioversion-resistant ventricular fibrillation (VF), until the use of intravenous amiodarone (AMD) was approved in 2007. The defibrillatory efficacy of NIF and AMD has thus far not been compared for resuscitation. Methods and Results: Between August 2007 and April 2009, 403 consecutive out-of-hospital patients with cardiopulmonary arrest were transferred to the Emergency Medical Service of Tokai University. Of these, 30 patients with first defibrillation failure or VF recurrence were enrolled for this NIF/AMD study. The final defibrillation success (and hospital survival rate) was 67% (10/15) in the AMD and 47% (7/15) in the NIF group. The discharge survival rate was 53% (8/15) in the AMD and 21% (4/15) in the NIF group (P = 0.06). Notably, all 4 survivors in the NIF group could take up normal daily life again, whereas this was restricted to only 2 patients from the 11 survivors in the AMD group. The difference is probably partly attributable to longer time from AMD administration to defibrillation success compared with NIF. In the cases of defibrillation failure, VF continued in 4/8 by NIF, however, asystole or pulseless electrical activity occurred in 4/5 patients by AMD. Conclusions: AMD may be borderline superior over NIF to facilitate defibrillation in out-of-hospital patients with cardiopulmonary arrest. However, from the view point of preservation of brain function, NIF is not inferior to AMD for CPR

In 2008, 1,007 cases of suicide in which hydrogen sulfide was used as a suicidal agent were reported in Japan, and this has become a serious social problem. Here, we report the successful revival of a patient suffering from a severe disturbance of consciousness and respiratory failure caused by hydrogen sulfide poisoning; further, his condition was complicated by myocardial infarction. This is an important case where we examined the tendency toward improvement in myocardial damage in a patient in the acute phase of severe hydrogen sulfide poisoning who was treated for approximately 6 months.

We have previously reported that the defibrillation success rate of intravenous nifekalant hydrochloride (NIF), a pure IKr-channel (IKr: the rapid components of the delayed rectifier potassium current) blocker, was more than 75% for lidocaine-resistant ventricular tachycardia and fibrillation (VT/VF) in patients with out-of-hospital cardiopulmonary arrest (CPA). However, there was no effective treatment for the remaining 25% of patients in whom defibrillation was unsuccessful. We hypothesised that the combination therapy of NIF and left stellate ganglion block (LSGB) was useful for defibrillation in NIF-resistant VT/VF and investigated its efficacy in a retrospective study.We investigated sequentially 272 out-of-hospital CPA patients treated at Tokai University between April and December 2006. VT/VF occurred in 55 patients on arrival or during cardiopulmonary resuscitation (CPR). On the basis of our CPR algorithm, NIF was administered (0.15-0.3 mg/kg, i.v.) after the first direct-current cardioversion. NIF-resistant VT/VFs were observed in 15 out of 55 patients and LSGB was performed on 11 of these with administration of NIF. Sinus rhythm was restored in 7 patients following LSGB (64%) and complete recovery was achieved in 2 patients. In the non-LSGB group, however, all the patients died.The combination therapy of intravenous NIF and LSGB was useful for defibrillation in intractable VT/VF. It is a potential and innovative treatment strategy for IKr-channel blocker resistant VT/VF. (Cardiol J 2007; 14: 355-365).

Because nifekalant hydrochloride (NIF) displayed a superior defibrillating effect on ventricular tachycardia/fibrillation (VT/VF) in cardiopulmonary arrest (CPA) patients, despite some QT prolongation, its effect on transmural dispersion of repolarization (TDR) in the left ventricle (LV) in an animal model of CPA was investigated.Eight beagle dogs were created with a myocardial infarction under anesthesia, and then VT/VF induction by continuous stimulation and cardiopulmonary resuscitation (CPR) were repeated. NIF (0.3 mg/kg) was administered under acidotic conditions (pH 7.26). The QTc interval measured by Y-lead ECG showed no significant prolongation before and after NIF. The activation recovery interval (ARI) measured by 64-lead LV surface mapping showed minimum ARI prolongation (40%) by NIF without maximum ARI prolongation, and as a result the ARI dispersion decreased by 67%. The repolarization time (RPT) with the plunge electrode showed 13-19% prolongation in the subendocardium and subepicardium with CPR, but NIF prolonged the RPT in the middle layer alone (17%), and as a result Plunge-TDR decreased by 82% (n=8, p0.05).Administration of NIF during CPR decreased the TDR by RPT prolongation selectively in the middle layer. Because the subendocardial and subepicardial RPTs after CPR were already prolonged before NIF administration, it may have been the reason why the QT-prolonging effect of NIF was not reflected in the body surface ECG.

Background Early defibrillation of ventricular tachycardia and fibrillation (VT/VF) is an urgent and most important method of resuscitation for survival in cardiopulmonary arrest (CPA). We have previously reported that nifekalant (NIF), a specific IKr blocker developed in Japan, is effective for lidocaine (LID) resistant VT/VF in out-of-hospital CPA (OHCPA). However, little is known about the differences in the effect of NIF on OHCPA with acidosis and in-hospital CPA (IHCPA) without acidosis. Methods and Results The present study enrolled 91 cases of DC shock resistant VT/VF among 892 cases of CPA that occurred between June 2000 and May 2003. NIF was used (0.15-0.3 mg/kg) after LID according to the cardiopulmonary resuscitation (CPR) algorithm of Tokai University. The defibrillation rate was higher in the NIF group for both OHCPA and IHCPA than for LID alone, and the VT/VF rate reduction effect could be maintained even with acidosis. However, sinus bradycardia in OHCPA, and torsades de pointes in IHCPA were occasionally observed. These differences in adverse effects might be related to the amount of epinephrine, serum potassium levels, serum pH, and interaction with LID. Conclusions NIF had a favorable defibrillating effect in both CPA groups, and it shows promise of becoming a first-line drug for CPR. (Circ J 2006; 70: 21 - 27)

Since the clinical profile and prognosis of heart failure depending on time of the study performed, regional characteristics of background population and different race, we attempted to evaluate the prognosis of symptoms and life expectancy of Japanese patients with heart failure. We evaluated the clinical profiles and prognoses of 1,015 consecutive patients with congestive heart failure (CHF) for whom hospitalization was required. A total of 1,015 consecutive CHF patients (584 males and 431 females) were enrolled in this study, however the total number of events investigated was 1,409. Of these patients, survival was confirmed in 413 patients, death was confirmed in 299 patients, and the prognoses of 303 patients remained unknown due to transfer to other hospitals or for some other reasons. The mean age on admission was 68.4 +/- 14.9 years. In both males and females, the peak age at the onset of CHF was in the seventies, and for patients in their eighties, the number of female patients with CHF was larger than that of male patients. Major underlying heart diseases consisted of ischemic heart disease (34%), valvular heart disease (22%), dilated cardiomyopathy (11%), and hypertension (10%). Most CHF patients who had dilated cardiomyopathy as an underlying disease were hospitalized several times, and 45% of them were hospitalized 3 times or more. The life expectancy of patients with CHF caused by ischemic heart disease was the poorest, and their 5-year and 10-year survival rates were 55% and 38%, respectively. Similarly, 5-year and 10-year survival rates of patients with CHF caused by valvular heart disease, hypertension, and dilated cardiomyopathy were 62% and 44%, 58% and 53%, and 70% and 65%, respectively. In 299 deceased patients, the mean age at death was 72.2 +/- 13.9 years. In all these deceased patients, direct causes of death were sudden death (16.1%), CHF (42.2%), others (31.4%), and unknown (10.4%). The frequency of sudden death was highest (25%) in patients with CHF caused by dilated cardiomyopathy, followed by those with CHF caused by valvular heart disease (18%) and those with CHF caused by ischemic heart disease (17.5%). In addition, the frequency of death from CHF was highest (60%) in those with CHF caused by dilated cardiomyopathy, followed by those with CHF caused by ischemic heart disease (49.2%).

Class I antiarrhythmic agents are not always effective in the treatment of life-threatening ventricular tachycardia/ventricular fibrillation (VT/VF) especially in patients with cardiopulmonary arrest. Nifekalant hydrochloride(NIF) is a novel class III antiarrhythmic agent for malignant VT/VF. This study prospectively evaluated NIF efficacy for life-threatening VT/VF observed after cardiopulmonary arrest.Thirty-two of 145 patients who were transferred to the emergency room in Tokai University Hospital showed VT/VF after resuscitation from cardiopulmonary arrest from June 2000 to March 2001. These 32 patients were treated with 12 mg (mean) epinephrine and 1.0-2.0 mg/kg lidocaine following direct current application(200 to 360J), and then classified into two groups. Eleven patients received intravenous 0.15 to 0.3 mg/kg NIF followed by intravenous infusion of 0.3 to 0.4 mg/kg/hr NIF(NIF group). The other 21 patients received 1.0 to 2.0 mg/kg of lidocaine(non-NIF group).Sinus rhythm was restored in the nine patients(82%) in the NIF group but only four patients (19%) in the non-NIF group. QTc was not prolonged(0.45 +/- 0.04 sec, n = 9) and no torsades de pointes was observed in the NIF group. Two patients survived but the remaining nine patients died in the NIF group. Five patients died of cardiac standstill following sinus bradycardia and repeated sinus arrest within 2 to 27 hr after admission, two patients died of sudden cardiac arrest from sinus rhythm, and two patients died of persistent VT/VF. In contrast, all 21 patients in the non-NIF group died. Seventeen patients died of persistent VT/VF before hospitalization, one patient died of recurrent VT/VF, and three patients died of cardiac standstill following sinus bradycardia.NIF effectively suppresses VT/VF which is refractory to direct current shock in patients with cardiopulmonary arrest. However, NIF may rather worsen electrophysiological function in the sinus node after administration of high doses of epinephrine, and may induce sinus bradycardia and/or sinus arrest. Careful observation, such as monitoring of electrocardiography and blood pressure and temporary cardiac pacemaker use, is needed to prevent death in patients surviving after cardiopulmonary arrest if NIF is administered following high dose epinephrine infusion.

Previous studies have revealed that the sympathetic nervous system is more vulnerable to ischemia than the myocardium itself. Thus our study was undertaken to detect denervated myocardium in non-Q-wave myocardial infarction (MI) and unstable angina with iodine 123 metaiodobenzylguanidine (123I-MIBG), which can delineate myocardial sympathetic innervation. Eight patients with non-Q-wave MI and 12 with unstable angina were studied. Sequential 123I-MIBG and thallium-201 chloride (201TlCl) imaging and single-photon emission computed tomography (SPECT) were performed at rest 24 +/- 12 days after the last ischemic attack. Myocardial perfusion defect was not detected by 201TlCl in 4 of 8 patients with non-Q-wave MI, whereas 123I-MIBG SPECT imaging revealed defects corresponding to myocardial ischemic areas predicted by coronary angiography in all 8 patients. 123I-MIBG imaging revealed defects in 7 of 12 patients with unstable angina corresponding to coronary angiographic findings, whereas no myocardial perfusion defect was detected by 201TlCl imaging in any of them. In conclusion, 123I-MIBG SPECT is a sensitive method for detecting myocardium exposed to transient ischemia that cannot be detected by 201TlCl imaging.