Eiichi Watanabe

Autoregressive (AR) models have been used in heart rate variability (HRV) analysis. In the conventional AR model, a Gaussian noise with a homogeneous variance are assumed to be the driving stochastic force. If this assumption is reasonable for the observed HRV time series, the HRV dynamics is fully characterized by its power spectrum. However, reasonability of the assumption has not been systematically examined. To address this problem, we studied variance heterogeneity, called heteroscedasticity, of HRV using a generalized autoregressive conditional heteroscedasticity (GARCH) model. In this study, we analyzed 24 hour HRV time series measured in healthy subjects (n=171) and in congestive heart failure (CHF) patients (n=108), and estimate the parameters of the GARCH model from the observed time series. In both healthy and CHF groups, variance heterogeneity of the HRV time series was observed. Furthermore, we found a statistically significant difference on the estimated parameters of the GARCH model between healthy and CHF groups.

BACKGROUND: Cardiac involvement is a leading cause of death from sarcoidosis. Because the efficacy of corticosteroid treatment is limited in patients with cardiac manifestation, early diagnosis is important. However, cardiac involvement is difficult to identify at early stages and is often underdiagnosed. Therefore, this study aimed to identify electrocardiographic risk factors for cardiac events in patients with extracardiac sarcoidosis. METHODS: This prospective observational cohort study included 227 patients with extracardiac sarcoidosis who did not have any cardiac manifestation (age, 49 ± 17 years; women, 63%). We studied the association of electrocardiographic abnormalities with developing cardiac manifestations. RESULTS: During a follow-up of 6.3 ± 3.7 years, 11 patients developed cardiac events, including advanced atrioventricular block (4 patients), ventricular tachycardia (4 patients), and systolic dysfunction (3 patients). All patients had electrocardiographic abnormalities prior to the development of cardiac events. In multivariate analyses, the baseline heart rate and PR interval were associated with increased risk of developing cardiac events. The QRS duration and corrected QT interval were not associated with cardiac manifestations. The multivariate analyses also revealed that baseline conduction disorder, ST segment/T wave abnormalities, and fragmented QRS complexes were associated with cardiac events. CONCLUSIONS: Electrocardiographic abnormalities occurred prior to cardiac events in extracardiac sarcoidosis. Patients with electrocardiographic abnormalities may require further evaluation for cardiac involvement and careful follow-up.

BACKGROUND: Atrial fibrillation (AF) is a significant risk factor for ischemic strokes, and making a robust risk stratification scheme would be important. Few studies have examined whether nonlinear dynamics of the heart rate could predict ischemic strokes in AF. We examined whether a novel complexity measurement of the heart rate variability called multiscale entropy (MSE) was a useful risk stratification measure of ischemic strokes in patients with permanent AF. METHODS AND RESULTS: We examined 173 consecutive patients (age 69 ± 11 years) with permanent AF who underwent 24-hour Holter electrocardiography from April 2005 to December 2006. We assessed several frequency ranges of the MSE and CHA2DS2-VASc score (1 point for congestive heart failure, hypertension, diabetes, vascular disease, an age 65 to 74 years, and a female sex and 2 points for an age ≥ 75 years and a stroke or transient ischemic attack). We found 22 (13%) incident ischemic strokes during a mean follow up of 3.8-years. The average value of the MSE in the very-low frequency subrange (90-300 s, MeanEnVLF2) was significantly higher in patients who developed ischemic strokes than in those who did not (0.68 ± 0.15 vs. 0.60±0.14, P<0.01). There was no significant difference in the C-statistic between the CHA2DS2-VASc score and MeanEnVLF2 (0.56; 95% confidence interval, 0.43-0.69 vs. 0.66; 95% confidence interval, 0.53-0.79). After an adjustment for the age, CHA2DS2-VASc score, and antithrombotic agent, a Cox hazard regression model revealed that the MeanEnVLF2 was an independent predictor of an ischemic stroke (hazard ratio per 1-SD increment, 1.80; 95% confidence interval, 1.17-2.07, P<0.01). CONCLUSION: The MeanEnVLF2 in 24-hour Holter electrocardiography is a useful risk stratification measure of ischemic strokes during the long-term follow-up in patients with permanent AF.

Background Dyspepsia (including upper abdominal pain, abdominal pain, abdominal discomfort, epigastric discomfort, and dyspepsia) is a symptom that is carefully monitored during dabigatran treatment. However, detailed information on dyspepsia, including onset, duration, severity, and use of drug treatment, has not yet been established in Japanese patients. Copy 2014 Japanese Heart Rhythm Society. Methods We conducted a multi-center, prospective, open-label, randomized, and parallel-group-comparison observational study of 309 patients with non-valvular atrial fibrillation who had been newly prescribed dabigatran at 19 institutes in Japan. Gastrointestinal adverse events were evaluated using the Global Overall Severity (GOS) scale self-reports to describe symptoms and to assess frequency and severity of symptoms (Part 1). Thereafter, patients with a GOS score ≥3 were randomized to receive a 4-week course of a proton pump inhibitor, an H2-receptor antagonist or a gastric mucosal protective drug (Part 2). Results The incidence of dyspepsia symptoms due to dabigatran was 17.2% (53/309, 95% confidence interval 13.1-21.8%), with 77% of events occurring within 10 days of initiation. Five patients discontinued the study because of dyspepsia. At the end of the observation period, the mean GOS score of those reporting dyspepsia was 3.5±1.7, with 11.3% (35/309) reporting a score ≥3. Substantial differences in the incidence of dyspepsia were observed between the study institutes (0-41%). In the multivariate regression analysis, no significant factor was found to affect incidence or severity of dyspepsia. The majority (83-100%) reported that symptoms improved with treatment (GOS score ≤), and there was no significant difference between the three different treatment groups. Conclusions The reported symptoms of dyspepsia were generally mild, but were moderate in approximately 10% of patients. Proton pump inhibitors, H2-receptor antagonists, and rebamipide seemed to be equally effective in relieving dabigatran-related dyspepsia (umin-CTR UMIN000007579).

OBJECTIVE: Lesions in the medulla oblongata may be causally associated with cardiac wall motion abnormality (WMA). Although subarachnoid hemorrhage (SAH) patients occasionally develop WMA, the relationship between aneurysmal locations and the frequency of WMA has rarely been investigated. The objective of this study was to evaluate whether the frequency of WMA was higher after the rupture of vertebral artery (VA) aneurysms than that of non-VA aneurysms. METHODS: We performed a retrospective chart analysis of 244 SAH patients who underwent transthoracic echocardiography and plasma catecholamine measurements. The frequencies of WMA and electrocardiographic (ECG) abnormalities were compared among patients classified by the location of aneurysms. Multivariate regression analysis was conducted to identify variables correlated with WMA. Furthermore, the relationship between plasma catecholamine levels and aneurysmal locations was evaluated. RESULTS: The frequency of WMA was significantly higher in patients with VA aneurysms than in those with non-VA aneurysms (45 vs. 22 %, p = 0.01). However, there was no significant difference in the frequency of ECG abnormalities. Multivariate regression analysis showed that VA aneurysms (OR, 3.317; 95 % CI, 1.129-9.745), poor-grade SAH (OR, 2.733; 95 % CI, 1.320-5.658) and concomitant hydrocephalus (OR, 3.658; 95 % CI, 1.690-7.917) correlated with WMA. There were no significant intergroup differences in plasma catecholamine levels. CONCLUSION: VA aneurysms are close to several medullary nuclei that integrate autonomic inputs. A transient deformation and ischemia of the medulla oblongata caused by the mechanical stress related to the rupture of a VA aneurysm and/or a concomitant hydrocephalus may be responsible for the disproportionately high frequency of WMA.

This study proposes a new method of urine flow measurement by image processing. There are problems of existing uroflowmeters such as the high price and the possibility of nosocomial infection when using cups. This study aims to estimate the flow rate and volume of urine simulated liquid discharged in air by using only one camera. Continuous pictures of liquid were imaged for extracting parameters including initial velocity of liquid. We estimated the volume of liquid based on multiple cylindrical model. From the experiment, the average estimation accuracy was within the range of 3%. This result showed the possibility of applying this method for urine volume estimation. Furthermore, this method includes the output of urinary flow rate curve. This study proposed a new method of simple urine flow management.

BACKGROUND: Causative arrhythmias of sudden cardiac arrest (SCA) are changing in this age of improved coronary care. OBJECTIVE: The purpose of this study was to examine the frequency of terminal arrhythmias and the electrical events prior to SCA. METHODS: We analyzed 24-hour Holter recordings of 132 patients enrolled from 41 institutions who either died (n = 88) or had an aborted death (n = 44). The Holter recordings were obtained for diagnosing and evaluating diseases and arrhythmias in those without any episodes suggestive of SCA. RESULTS: In 97 patients (73%), SCA was associated with ventricular tachyarrhythmias and in 35 (27%) with bradyarrhythmias. The bradyarrhythmia-related SCA patients were older than those with a tachyarrhythmia-related SCA (70 ± 13 years vs. 58 ± 19 years, P < .001). The most common arrhythmia for a tachyarrhythmia-related SCA was ventricular tachycardia degenerating to ventricular fibrillation (45%). The bradyarrhythmia-related SCA was caused by asystole (74%) or AV block (26%). Spontaneous conversion was observed in 37 patients (38%) with ventricular tachyarrhythmias. Of those, 62% of the patients experienced symptoms including syncope, chest pain, or convulsion. Multivariate logistic analysis revealed that independent predictors of mortality for tachyarrhythmia-related SCAs were advanced age (odds ratio 1.04, 95% confidence interval 1.02-1.08) and ST elevation within the hour before SCA (odds ratio 3.54, 95% confidence interval 1.07-13.5). In contrast, the presence of preceding torsades de pointes was associated with spontaneous conversion (odds ratio 0.20, 95% confidence interval 0.05-0.66). CONCLUSION: The most frequent cause of SCA remains ventricular tachyarrhythmias. Advanced age and ST elevation before SCA are risk factors for mortality in tachyarrhythmia-related SCAs.

BACKGROUND: Paroxysmal atrial fibrillation (AF) patients have a reduced quality-of-life (QoL) despite the fact that the majority of AF episodes are asymptomatic. Asymptomatic AF is likely to be associated with substantial morbidity and mortality rates similar to those with symptomatic AF, whereas its effect on the QoL has not yet been clarified. PURPOSE: We studied the specific contribution of asymptomatic AF episodes to reducing the QoL. METHODS: We assessed the QoL in 233 patients with paroxysmal AF and hypertension (age 64.9 ± 9.7 years, 71% male) enrolled in the Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II study) using an AF-specific QoL questionnaire (AFQLQ). The AFQLQ comprised 3 components: AFQLQ1, the frequency and duration of symptoms; AFQLQ2, severity of symptoms; and AFQLQ3, limitations in daily activities and mental anxiety. Higher scores indicated a better QoL. Each patient transmitted electrocardiograms for 30s daily at a predetermined time as well as whenever arrhythmia-related symptoms were experienced. We examined the relationship between the 3 AFQLQ components and frequency of symptomatic and asymptomatic AF episodes (days/month) during 12 months of follow-up. RESULTS: The symptomatic and asymptomatic AF frequencies were 0.9 ± 3.1 days/month and 1.5 ± 3.5 days/month, respectively. AFQLQ1 negatively correlated with the symptomatic AF frequency (Spearman's correlation coefficient: r = -0.332, p < 0.001). AFQLQ2 and AFQLQ3 correlated with both the symptomatic AF frequency (r = -0.27, p < 0.001 and r = -0.265, p < 0.001, respectively) and asymptomatic AF frequency (r = -0.197, p < 0.01 and r = -0.229, p < 0.005, respectively). CONCLUSION: The asymptomatic AF episode frequency correlates with a reduced QoL in patients with paroxysmal AF, suggesting that there would be psychological benefits to its reduction.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia; however, little is known about patients in a primary care setting from high-, middle-, and low-income countries. METHODS AND RESULTS: This prospective registry enrolled patients presenting to an emergency department with AF at 164 sites in 46 countries representing all inhabited continents. Patient characteristics were compared among 9 major geographic regions. Between September 2008 and April 2011, 15,400 patients were enrolled. The average age was 65.9, standard deviation 14.8 years, ranging from 57.2, standard deviation 18.8 years in Africa, to 70.1, standard deviation 13.4 years in North America, P<0.001. Hypertension was globally the most common risk factor for AF, ranging in prevalence from 41.6% in India to 80.7% in Eastern Europe, P<0.001. Rheumatic heart disease was present in only 2.2% of North American patients, in comparison with 21.5% in Africa and 31.5% in India, P<0.001. The use of oral anticoagulation among patients with a CHADS2 score of ≥2 was greatest in North America (65.7%) but was only 11.2% in China, P<0.001. The mean time in the therapeutic range was 62.4% in Western Europe, 50.9% in North America, but only between 32% and 40% in India, China, Southeast Asia, and Africa, P<0.001. CONCLUSIONS: There is a large global variation in age, risk factors, concomitant diseases, and treatment of AF among regions. Improving outcomes globally requires an understanding of this variation and the conduct of research focused on AF associated with different underlying conditions and treatment of AF and predisposing conditions in different socioeconomic settings.

Treatment guidelines for atrial fibrillation (AF) used in Western countries describe female gender as a risk factor for thromboembolic events in patients with nonvalvular AF (NVAF). The present study aimed to determine the impact of gender on prognosis of Japanese patients with NVAF. A subanalysis of 7,406 patients with NVAF (mean age 70 years) who were followed-up prospectively for 2 years was performed using data from the J-RHYTHM registry. The primary end points were thromboembolic events, major hemorrhaging, total mortality, and cardiovascular mortality. Compared with male subjects (n = 5,241), female subjects (n = 2,165) were older and displayed greater prevalences of paroxysmal AF, heart failure, and hypertension but less prevalences of diabetes, previous cerebral infarction, and coronary artery disease. Male and female patients had mean CHADS2 (Congestive heart failure, Hypertension, Age of 75 years or more, Diabetes mellitus and prior Stroke or transient ischemic attack) scores of 1.6 and 1.8, respectively (p <0.001). Warfarin was given to 87% of male patients and 86% of female patients (p = 0.760), and the 2 genders displayed similar mean international normalized ratio of prothrombin time values at baseline (1.91 vs 1.90, respectively, p = 0.756). Multivariate logistic regression analysis indicated that male gender was an independent risk factor for major hemorrhaging (odds ratio 1.59, 95% confidence interval 1.05 to 2.40, p = 0.027) and all-cause mortality (odds ratio 1.78, 95% confidence interval 1.25 to 2.55, p <0.002) but not for thromboembolic events (odds ratio 1.24, 95% confidence interval 0.83 to 1.86, p = 0.297) or cardiovascular mortality (odds ratio 0.96, 95% confidence interval 0.56 to 1.66, p = 0.893). In conclusion, female gender is not a risk factor for thromboembolic events among Japanese patients with NVAF who were treated mostly with warfarin. However, male gender is a risk factor for major hemorrhaging and all-cause mortality.

A priori discrimination of high mortality risk amongst congestive heart failure patients constitutes an important clinical stake in cardiology and involves challenging analyses of the temporal dynamics of heart rate variability (HRV). The present contribution investigates the potential of a new multifractal formalism, constructed on wavelet p-leader coefficients, to help discrimination between survivor and non survivor patients. The formalism, applied to a high quality database of 108 patients collected in a Japanese hospital, enables to assess the existence of multifractal properties amongst congestive heart failure patients and to reveal significant differences in the multiscale properties of HRV between survivor and non survivor patients, for scales ranging from approximately 60 to 250 beats.

BACKGROUND AND PURPOSE: Insular injuries are known to cause autonomic derangements. Patients with ruptured middle cerebral artery aneurysms frequently develop temporal hematomas (THs) in addition to subarachnoid hemorrhages, and those with TH may sustain autonomic derangements more frequently than those without TH. Hemispheric lateralization in autonomic derangements has been reported in patients with insular ischemic stroke, and this study was conducted to clarify whether such lateralization was also observed in patients with TH resulting from middle cerebral artery aneurysm rupture. METHODS: A retrospective analysis on the medical records of 79 patients with ruptured middle cerebral artery aneurysms was performed on the basis of lateralization and presence of TH. They were quadrichotomized as left TH+ (LTH+; n=17), right TH+ (n=25), left TH- (n=15), and right TH- (n=22). Comparisons, mainly between LTH+ and right TH+, were made on demographic variables, autonomic/cardiac parameters, plasma catecholamine and glucose levels, and outcomes. RESULTS: There were no significant differences in demographic or cardiac parameters between the 2 groups. Systolic blood pressures were lower in LTH+ (139±34 versus 174±47 mm Hg; P=0.05). The LTH+ group also tended to be more bradycardiac (80±19 versus 101±22 bpm; P=0.13). The LTH+ group exhibited significantly lower plasma norepinephrine (1008±975 versus 2549±2133 pg/mL; P=0.03) and glucose levels (9.3±1.8 versus 12.2±4.5 mmol/L; P=0.04). However, in-hospital mortality did not differ significantly (41% versus 44%; P=1.00). CONCLUSIONS: Lateralization of autonomic derangements observed might not have had a significant effect on the outcomes. Nevertheless, autonomic derangements associated with insular injury should be considered in the management of subarachnoid hemorrhage patients with TH.

AIMS: We examined whether the severity of central sleep apnoea (CSA) and the level of C-reactive protein are associated with the prevalence and complexity of arrhythmias, and whether these factors contribute to increased risk of nocturnal sudden death. METHODS AND RESULTS: We prospectively examined 178 patients (age 70 ± 1 years) who were admitted to our hospital due to worsening heart failure. We recorded a simultaneous overnight cardiorespiratory polygraph and Holter ECG. Obstructive sleep apnoea was excluded and patients were dichotomized based on the median value of the central apnoea index (CAI) of 7.5/h. The prevalence and complexity of arrhythmias were compared between daytime (06:00 h to 15:00 h) and night-time (21:00 h to 06:00 h). A multivariate logistic regression analysis revealed that the CAI was associated with prevalence of atrial fibrillation (AF) [odds ratio 1.03, 95% confidence interval (CI) 1.02-2.51)] and sinus pause during the night-time period (1.12, 95% CI 1.08-1.35). The CAI and C-reactive protein were independently associated with non-sustained ventricular tachycardia during both daytime (1.22, 95% CI 1.00-6.92; and 5.82, 2.58-56.1, respectively) and night-time periods (3.57, 95% CI 1.06-13.1; and 10.7, 3.30-44.4, respectively). During a mean follow-up period of 22 months, 30 (17%) patients had cardiovascular deaths and the CSA was an independent predictor (hazard ratio 1.29, 95% CI 1.16-2.32); only 5 (2.8%) of them died due to ventricular tachyarrhythmia, occurring during wakefulness. CONCLUSIONS: We demonstrated that the severity of CSA and C-reactive protein levels are independently associated with the prevalence and complexity of arrhythmias. CSA was associated with increased mortality risk, but it was not related directly to nocturnal death due to ventricular tachyarrhythmia.

Significant circadian variations exist in the frequency of cardiac arrhythmia, but few studies have examined the relation between cardiac ion channels genes and biological clocks. We investigated this relation using suprachiasmatic nuclei lesion (SCNX) and pharmacological autonomic nervous system block (ANSB) mice. Significant 24-h variations were observed in the expression of clock genes Per2, Bmal1, and Dbp and ion channel genes KCNA5, KCND2, KCHIP2, and KCNK3 in the control mice hearts. In the SCNX mice, all genes examined lost circadian rhythm. In the ANSB mice, the expressions of the three clock genes were dampened significantly but still had circadian rhythm, whereas the four ion channel gene expressions lost rhythm. Heart rate also lost circadian rhythm in both the SCNX and ANSB mice. These results suggest that some ion channel gene expressions might be regulated by the central clock in the SCN through the ANS but not the peripheral clock in the heart.

Patients with aneurysmal subarachnoid hemorrhage (SAH) are frequently complicated by acute cardiac dysfunctions, including cardiac wall motion abnormality (WMA). Massive release of catecholamine into the systemic circulation after aneurysmal rupture is believed to result in WMA, and poor-grade SAH seems to be the most important risk factor. However, plasma catecholamine levels have rarely been measured in SAH patients with WMA, and previous studies indicated that the elevated levels might not necessarily predict WMA. The objective of this study is (1) to evaluate relationship between WMA and plasma catecholamine levels in poor-grade SAH patients in the acute phase and (2) to clarify clinical characteristics of SAH patients with WMA. Among 142 poor-grade (World Federation of Neurosurgical Societies grades IV and V) SAH patients, 48 underwent both transthoracic ultrasound and measurement of plasma catecholamine levels within 24 h of SAH onset. They were divided into WMA+ (n = 23) and WMA- (n = 25) groups, and intergroup comparison was made on demographics, plasma catecholamine levels, and outcomes. Plasma norepinephrine levels were significantly higher in WMA+ group than in WMA- group (2,098.4 ± 1,773.4 vs. 962.9 ± 838.9 pg/mL, p = 0.02), and the former showed significantly worse outcomes 90 days after admission. There were no intergroup differences in the plasma levels of epinephrine. Plasma norepinephrine levels were inversely correlated with left ventricular ejection fraction. Multivariate logistic regression analysis revealed that increased plasma norepinephrine levels were predictive of WMA, although age, female sex, and grade V SAH were not. This retrospective study highlights the role of norepinephrine in pathogenesis of SAH-induced WMA.

PURPOSE: Sleep-disordered breathing (SDB) is associated with increased risk for cardiovascular morbidity and mortality and for sleepiness-related accidents, but >75 % of the patients remain undiagnosed. We sought to determine the diagnostic accuracy of ECG-based detection of SDB when used for population-based screening. METHODS: All male workers, mostly truck drivers, of a transport company (n = 165; age, 43 ± 12 years) underwent standard attended overnight polysomnography. Cyclic variation of heart rate (CVHR), a characteristic pattern of heart rate associated with SDB, was detected from single-lead ECG signals during the polysomnography by a newly developed automated algorithm of autocorrelated wave detection with adaptive threshold (ACAT). RESULTS: Among 165 subjects, the apnea-hypopnea index (AHI) was ≥5 in 62 (38 %), ≥15 in 26 (16 %), and ≥30 in 16 (10 %). The number of CVHR per hour (CVHR index) closely correlated with AHI [r = 0.868 (95 % CI, 0.825-0.901)]. The areas under the receiver operating characteristic curves for detecting subjects with AHI ≥5, ≥15, and ≥30 were 0.796 (95 % CI, 0.727-0.855), 0.974 (0.937-0.993), and 0.997 (0.971-0.999), respectively. With a predetermined criterion of CVHR index ≥15, subjects with AHI ≥15 were identified with 88 % sensitivity and 97 % specificity (likelihood ratios for positive and negative test, 30.7 and 0.12). The classification performance was retained in subgroups of subjects with obesity, hypertension, diabetes mellitus, dyslipidemia, and decreased autonomic function. CONCLUSIONS: The CVHR obtained by the ACAT algorithm may provide a useful marker for screening for moderate-to-severe SDB among apparently healthy male workers.

BACKGROUND: Target anticoagulation levels for warfarin in Japanese patients with non-valvular atrial fibrillation (NVAF) are unclear. METHODS AND RESULTS: Of 7,527 patients with NVAF, 1,002 did not receive warfarin (non-warfarin group), and the remaining patients receiving warfarin were divided into 5 groups based on their baseline international normalized ratio (INR) of prothrombin time (≤1.59, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0). Patients were followed-up prospectively for 2 years. Primary endpoints were thromboembolic events (cerebral infarction, transient ischemic attack, and systemic embolism), and major hemorrhage requiring hospital admission. During the follow-up period, thromboembolic events occurred in 3.0% of non-warfarin group, but at lower frequencies in the warfarin groups (2.0, 1.3, 1.5, 0.6, and 1.8%/2 years for INR values of ≤1.59, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0, respectively; P=0.0059). Major hemorrhage occurred more frequently in warfarin groups (1.5, 1.8, 2.4, 3.3, and 4.1% for INR values ≤1.59, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0, respectively; P=0.0041) than in non-warfarin group (0.8%/2 years). These trends were maintained when the analyses were confined to patients aged ≥70 years. CONCLUSIONS: An INR of 1.6-2.6 is safe and effective at preventing thromboembolic events in patients with NVAF, particularly patients aged ≥70 years. An INR of 2.6-2.99 is also effective, but associated with a slightly increased risk in major hemorrhage. (UMIN Clinical Trials Registry UMIN000001569)

BACKGROUND: Remote monitoring (RM) technology has emerged as a potentially efficient method to manage patients with implantable cardioverter defibrillators (ICDs) or cardiac resynchronization therapy defibrillators (CRT-Ds). This study evaluated the reliability of daily RM in forecasting the need for regular in-hospital follow-ups (RFUs). METHODS AND RESULTS: Two hundred and fifteen patients implanted with Biotronik Lumax devices (142 ICDs, 73 CRT-Ds) were enrolled. RFU was performed at 3, 6, 9, and 12 months after implantation. Immediately before an RFU, the physician forecasted the need for RFU based on RM data (pre-RFU assessment). A completed RFU session was classified as necessary if an action was undertaken potentially influencing patient safety, device therapy, or medication therapy (post-RFU assessment). Overall, 663 pairs of pre- and post-RFU assessments were compared. The number of pre-RFU assessments failing to predict the need for RFU was 38 (5.7%), fulfilling the study hypothesis of 5.0±4.0% (P<0.002; 95% confidence interval: 4.1-7.8%). Judged by an independent committee, the rate of false pre-RFU forecasts with high clinical relevance was 2 (0.3%). RM correctly forecasted non-necessity of 498 scheduled RFUs (75.1%). Patient acceptance of RM was evaluated using a targeted questionnaire. Of 182 interviewed patients, 172 (94.5%) felt security and comfort. CONCLUSIONS: RM-based forecasts appear sufficiently accurate to safely individualize RFU. Most patients have a positive attitude towards RM.

OBJECTIVE: Depression and sleep apnea (SA) are common among patients with a recent acute myocardial infarction (AMI), and both are associated with increased risk for adverse outcomes. We tested the hypothesis that there is an interaction between them in relation to post-AMI prognosis. METHODS: Participants were patients with a recent AMI, 337 of them were depressed and 379 were nondepressed, who participated in a substudy of the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial. SA was identified from Holter electrocardiogram by an algorithm that detects cyclic variation of heart rate. RESULTS: During a median follow-up of 25 months, 83 (11.6%) patients either died or experienced a recurrent AMI and 43 (6.0%) patients died. Among 94 patients with both depression and SA, these end points occurred in 25 (26.6%) and 20 (21.3%) at 3.9- and 6.9-times higher prevalence than predicted probabilities by ENRICHD clinical risk scores (p <.001 for both). In the patients with depression alone, SA alone, or neither, the prevalence was similar to the predicted probability. Depression and SA showed significant interactions in prediction of these end points (p = .02 and p = .03). SA independently predicted these end points in patients with depression (p = .001 and p <.001) but not in those without depression (p = .84 and p = .73). Similarly, depression independently predicted these end points in patients with SA (p <.001 for both) but not in those without SA (p = .12 and p = .61). CONCLUSIONS: Depression and SA are interactively associated with adverse clinical outcomes after AMI. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00313573.

BACKGROUND AND PURPOSE: The majority of patients with ventricular wall motion abnormality (WMA) associated with subarachnoid hemorrhage (SAH) are postmenopausal women. In addition to elevated catecholamine, the role of estrogen in the pathogenesis of WMA has recently been implicated. The objective of this study is to clarify the interrelation among catecholamine, estrogen, and WMA in patients with SAH. METHODS: A retrospective analysis was performed on the medical records of 77 patients with SAH (23 men, 54 women) whose plasma levels of epinephrine, norepinephrine, and estradiol had been measured and echocardiograms had been obtained within 48 hours of SAH onset. RESULTS: Twenty-four patients (31%) were found to sustain WMA on admission. Multivariate regression analysis revealed that decreased estradiol (P=0.018; OR, 0.902) and elevated norepinephrine levels (P=0.027; OR, 1.002) were associated with WMA. After quadrichotomization of 77 patients based on sex/WMA, plasma norepinephrine levels were markedly elevated in men with WMA, whereas estradiol levels were markedly decreased in women with WMA. Plasma norepinephrine and estradiol levels were not correlated. Fifty-four female patients with SAH were further quadrichotomized based on norepinephrine/estradiol levels with a threshold value of 1375 pg/mL for norepinephrine and 11 pg/mL for estradiol. The incidence of WMA in the high-norepinephrine/low-estradiol group was significantly higher than the low-norepinephrine/high-estradiol group. CONCLUSIONS: To our knowledge, this is the first study to evaluate the interrelation among catecholamine, estrogen, and SAH-induced WMA. Lack of estradiol in postmenopausal women may predispose them to develop WMA after poor-grade SAH. However, the precise role of multiple sex hormones in SAH-induced WMA should be evaluated in future prospective studies.

BACKGROUND: Atrial fibrillation (AF) and heart failure (HF) are associated with significant mortality and morbidity. We sometimes encounter patients who have AF upon admission to the hospital, but it spontaneously converts to sinus rhythm within several days (i.e. converter). PURPOSE: We examined the association between the outcome and types of strategy for AF treatment in converters. METHODS: From January 2000 to December 2005, we identified 95 converters (age 69 ± 12 years) presenting with worsening HF and AF upon admission, in which sinus rhythm was restored within 7 days without either electrical or pharmacological cardioversion. The patients were classified into three groups according to the antiarrhythmic drug (AAD) therapy used: class I AAD, class III AAD, and rate-control drug. The patients were followed for 36 ± 23 months. RESULTS: The left ventricular ejection fraction (LVEF) significantly improved with conversion to sinus rhythm (38 ± 14% vs. 47 ± 13%, p<0.05). Those receiving class I AAD had a trend toward a well-preserved LVEF (50 ± 13%, n=35) as compared to those receiving class III AAD (43 ± 12%, n=24) or rate-control drug (47 ± 14%, n=36). In the patients receiving class I AAD, the rate of all-cause death increased 1.9-fold (p=0.009) compared to those receiving class III AAD, and 1.7-fold (p=0.010) compared to those taking rate-control drug. A hospitalization for HF was observed in 49 (52%) patients, however there was no significant difference in the rate of hospitalization among the three groups (p=0.890). Those receiving rate-control drugs had a 50% lower rate of the development of persistent AF than those taking class III AAD (p=0.019). CONCLUSIONS: A rate-control strategy should be the primary approach for converters to reduce mortality and development of persistent AF.

The correlates of indices of long-term ambulatory heart rate variability (HRV) of the autonomic nervous system have not been completely understood. In this study, we evaluated conventional HRV indices, obtained from the daytime (12:00-18:00) Holter recording, and a recently proposed non-Gaussianity index (λ; Kiyono et al., 2008) in 12 patients with multiple system atrophy (MSA) and 10 patients with Parkinson disease (PD), known to have varying degrees of cardiac vagal and sympathetic dysfunction. Compared with the age-matched healthy control group, the MSA patients showed significantly decreased HRV, most probably reflecting impaired vagal heart rate control, but the PD patients did not show such reduced variability. In both MSA and PD patients, the low-to-high frequency (LF/HF) ratio and the short-term fractal exponent α(1), suggested to reflect the sympathovagal balance, were significantly decreased, as observed in congestive heart failure (CHF) patients with sympathetic overdrive. In contrast, the analysis of the non-Gaussianity index λ showed that a marked increase in intermittent and non-Gaussian HRV observed in the CHF patients was not observed in the MSA and PD patients with sympathetic dysfunction. These findings provide additional evidence for the relation between the non-Gaussian intermittency of HRV and increased sympathetic activity.

AIMS: Increased temporal repolarization lability, assessed by beat-to-beat variability of T-wave amplitude (TAV), has been shown to be associated with ventricular tachyarrhythmia in patients with a variety of clinical conditions. The aim of this study was to test the ability of TAV to identify patients presenting with malignant ventricular arrhythmia and to predict subsequent occurrences. METHODS AND RESULTS: We studied 20 consecutive patients (age 42 ± 15 years, mean ± standard deviation) presenting with ventricular tachyarrhythmia who did not have substantial underlying heart disease and compared them with 40 age- and sex-matched control subjects. The TAV was determined by Holter recording (Ela Medical). Patients with ventricular tachyarrhythmia had a higher maximum value of TAV (max TAV: 38 ± 18 vs. 22 ± 15 μV, P < 0.001) than did the controls. The sensitivity and specificity of max TAV > 22.4 μV for detecting the occurrence of ventricular tachyarrhythmia were 77 and 90%, respectively. During a mean follow-up period of 23 months, three patients had relapses of ventricular tachyarrhythmia. Patients with a recurrence of ventricular tachyarrhythmia had a trend towards a higher max TAV as compared with those who had ventricular tachyarrhythmia but did not relapse (56 ± 23 vs. 36 ± 16 μV, P = 0.061). CONCLUSION: Our results suggest that Holter-derived TAV might be associated with the occurrence and recurrence of ventricular tachyarrhythmia in patients without structural heart disease. Prospective validation will be necessary to assess the potential diagnostic value of the TAV in a large general population.

BACKGROUND: n-3 polyunsaturated fatty acids, primarily eicosapentaenoic acid (EPA), has been reported to have antiarrhythmic and antiinflammatory effects. The aim of the present study was to examine whether the combination of antiarrhythmic drugs and EPA reduced the frequency of atrial fibrillation (AF) in patients with paroxysmal AF. METHODS: We studied 50 patients with paroxysmal AF (age, 54 ± 9 years) after excluding the clinical conditions associated with an increased risk of AF. Patients were initially treated with antiarrhythmic drugs for 6 months (the observation period), and thereafter, EPA was added at a dose of 1.8 g/day for 6 months (the intervention period). During a one-year period, patients obtained an ECG recording using a portable device each morning and when arrhythmia-related symptom occurred. The end point was the difference of the AF burden (defined by the days of AF per month) between observation period and intervention period. Plasma EPA and C-reactive protein (CRP) levels were also determined. RESULTS: There was no significant difference in the AF burden before and after intervention (2.6 ± 2.2 days/months vs. 2.5 ± 2.2 days/months, P = 0.45). Although EPA level was significantly increased (42 ± 15 μg/mL to 120 ± 47 μg/mL, P < 0.001), CRP level was unchanged (1.04 ± 0.69 mg/L to 0.96 ± 0.56 mg/L, P = 0.24) following EPA treatment. CONCLUSIONS: Treatment of EPA in combination with antiarrhythmic drugs did not reduce the AF burden or the CRP levels in paroxysmal AF patients who had no evidence of substantial structural heart disease.

BACKGROUND: Prolonged duration of the QRS complex is a prognostic marker in patients with heart failure (HF), whereas electrocadiographic markers in HF with narrow QRS complex remain unclear. We evaluated the prognostic value of the T-wave amplitude in lead aVR in HF patients with narrow QRS complexes. METHODS: We examined 331 patients who were admitted to our hospital for worsening HF (68 ± 15 years, mean ± standard deviation) from January 2000 to October 2004 who had sinus rhythm and QRS complex <120 ms. The patients were categorized into three groups according to the peak T-wave amplitude from baseline in lead aVR: negative (<-0.1 mV; n = 209, 63%), flat (-0.1-0.1 mV; n = 64, 19%), and positive (>0.1 mV; n = 58, 18%). RESULTS: During a mean follow-up of 33 months, 113 (34%) patients had all-cause death, the primary end point. After adjusting for clinical covariates, flat T wave (hazard ratio [HR] 1.86, 95% confidence interval [CI] 1.42-2.46), and positive T wave (HR 6.76, 95% CI 3.92-11.8) were independent predictors of mortality, when negative T wave was considered a reference. CONCLUSIONS: As the peak T-wave amplitude in lead aVR becomes less negative, there was a progressive increase in mortality. The T wave in lead aVR provides prognostic information for risk stratification in HF patients with narrow QRS complexes.

AIMS: Atrial fibrillation (AF) is a common arrhythmia frequently associated with hypertension. This study was designed to test the hypothesis that lowering blood pressure by angiotensin II-receptor blockers (ARB) has more beneficial effects than by conventional calcium channel blockers (CCB) on the frequency of paroxysmal AF with hypertension. METHODS AND RESULTS: The Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II study) is an open-label randomized comparison between an ARB (candesartan) and a CCB (amlodipine) in the treatment of paroxysmal AF associated with hypertension. Using daily transtelephonic monitoring, we examined asymptomatic and symptomatic paroxysmal AF episodes during a maximum 1 year treatment. The primary endpoint was the difference in AF frequency between the pre-treatment period and the final month of the follow-up. The secondary endpoints included cardiovascular events, development of persistent AF, left atrial dimension, and quality-of-life (QOL). The study enrolled 318 patients (66 years, male/female 219/99, 158 in the ARB group and 160 in the CCB group) treated at 48 sites throughout Japan. At baseline, the frequency of AF episodes (days/month) was 3.8 ± 5.0 in the ARB group vs. 4.8 ± 6.3 in the CCB group (not significant). During the follow-up, blood pressure was significantly lower in the CCB group than in the ARB group (P < 0.001). The AF frequency decreased similarly in both groups, and there was no significant difference in the primary endpoint between the two groups. There were no significant differences between the two groups in the development of persistent AF, changes in left atrial dimension, occurrence of cardiovascular events, or changes in QOL. CONCLUSIONS: In patients with paroxysmal AF and hypertension, treatment of hypertension by candesartan did not have an advantage over amlodipine in the reduction in the frequency of paroxysmal AF (umin CTR C000000427).

BACKGROUND: Despite the adverse cardiovascular consequences of obstructive sleep apnea, the majority of patients remain undiagnosed. To explore an efficient ECG-based screening tool for obstructive sleep apnea, we examined the usefulness of automated detection of cyclic variation of heart rate (CVHR) in a large-scale controlled clinical setting. METHODS AND RESULTS: We developed an algorithm of autocorrelated wave detection with adaptive threshold (ACAT). The algorithm was optimized with 63 sleep studies in a training cohort, and its performance was confirmed with 70 sleep studies of the Physionet Apnea-ECG database. We then applied the algorithm to ECGs extracted from all-night polysomnograms in 862 consecutive subjects referred for diagnostic sleep study. The number of CVHR per hour (the CVHR index) closely correlated (r=0.84) with the apnea-hypopnea index, although the absolute agreement with the apnea-hypopnea index was modest (the upper and lower limits of agreement, 21 per hour and -19 per hour) with periodic leg movement causing most of the disagreement (P<0.001). The CVHR index showed a good performance in identifying the patients with an apnea-hypopnea index ≥15 per hour (area under the receiver-operating characteristic curve, 0.913; 83% sensitivity and 88% specificity, with the predetermined cutoff threshold of CVHR index ≥15 per hour). The classification performance was unaffected by older age (≥65 years) or cardiac autonomic dysfunction (SD of normal-to-normal R-R intervals over the entire length of recording <65 ms; area under the receiver-operating characteristic curve, 0.915 and 0.911, respectively). CONCLUSIONS: The automated detection of CVHR with the ACAT algorithm provides a powerful ECG-based screening tool for moderate-to-severe obstructive sleep apnea, even in older subjects and in those with cardiac autonomic dysfunction.

Cyclic variation of heart rate (CVHR) associated with sleep apnea/hypopnea episodes has been suggested as a marker of sleep disordered breathing (SDB). This study examined the utility of ECG-based CVHR detection for diagnosing SDB using simultaneous polysomnography as the reference standard. We used a previously developed automated CVHR detection algorithm (autocorrelated wave detection with adaptive threshold, ACAT) that provides the number of CVHR per hour (CVHR index). The ACAT was refined using a polysomnographic database of 194 subjects with various severities of SDB and then, applied to a single channel ECG obtained during standard overnight polysomnography in 862 consecutive subjects referred for SDB diagnosis. Using multiple thresholds of CVHR index ≥ 38 and <27, positive and negative predictive values of 95.6% and 95.1%, respectively, were achieved for detecting and excluding subjects with apnea-hypopnea index (AHI) ≥ 30, leaving 58 (6.7%) unclassified subjects. Positive and negative likelihood ratios (LRs) were 97.3 and 0.23, respectively. Also, thresholds of CVHR index ≥ 29 and <7 provided 96.1% and 95.1% of positive and negative predictive values, respectively, for subjects with AHI ≥ 15 (LRs, 50.6 and 0.11), leaving 426 (49.4%) unclassified subjects. The CVHR correlated with the AHI (r = 0.86) and showed the limits of agreement with the AHI of 19.6 and -18.6. Automated detection of CVHR by the ACAT algorithm provides useful screening tool for both increasing and decreasing probability of moderate and sever SDB with adequate thresholds.

Recent clinical evidence and animal experiments support the belief that statins have beneficial effects on cardiovascular outcomes and prevention of atrial fibrillation (AF). We investigated whether the use of statins reduces the mortality, morbidity, and recurrence rate of AF in patients with paroxysmal AF. A post hoc analysis of the Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM) study was conducted.Of the 823 patients with paroxysmal AF in the J-RHYTHM study, 101 (12.3%) were receiving a statin at baseline. Patients taking statins were older and more likely to have hypertension, dyslipidemia, coronary artery disease, and ischemic stroke compared to patients not taking statins. During a mean follow-up period of 19.3 months, 40 patients (5.5%) reached the primary endpoint (a composite of all-cause death, stroke, systemic embolism, major bleeding, and hospitalization for heart failure) and 140 patients (19.4%) experienced a recurrence of AF. Multivariate Cox proportional-hazard regression analysis revealed statin use was not associated with improved mortality and morbidity (hazard ratio [HR] 0.409, 95% confidence interval [CI] 0.113-1.482), or a decreased risk of AF recurrence (HR 0.662, 95% CI 0.299-1.466).This analysis provides evidence that statin use did not affect clinical outcomes in patients with paroxysmal AF and emphasizes the need for randomized clinical trials defining more clearly the role of statins in treating AF.

Non-Gaussianity index (λ) is a new index of heart rate variability (HRV) that characterizes increased probability of the large heart rate deviations from its trend. A previous study has reported that increased λ is an independent mortality predictor among patients with chronic heart failure. The present study examined predictive value of λ in patients after acute myocardial infarction (AMI). Among 670 post-AMI patients, we performed 24-h Holter monitoring to assess λ and other HRV predictors, including SD of normal-to-normal interval, very-low frequency power, scaling exponent α(1) of detrended fluctuation analysis, deceleration capacity, and heart rate turbulence (HRT). At baseline, λ was not correlated substantially with other HRV indices (|r| < 0.4 with either indices) and was decreased in patients taking β-blockers (P = 0.04). During a median follow-up period of 25 months, 45 (6.7%) patients died (32 cardiac and 13 non-cardiac) and 39 recurrent non-fatal AMI occurred among survivors. While all of these HRV indices but λ were significant predictors of both cardiac and non-cardiac deaths, increased λ predicted exclusively cardiac death (RR [95% CI], 1.6 [1.3-2.0] per 1 SD increment, P < 0.0001). The predictive power of increased λ was significant even after adjustments for clinical risk factors, such as age, diabetes, left ventricular function, renal function, prior AMI, heart failure, and stroke, Killip class, and treatment ([95% CI], 1.4 [1.1-2.0] per 1 SD increment, P = 0.01). The prognostic power of increased λfor cardiac death was also independent of all other HRV indices and the combination of increased λ and abnormal HRT provided the best predictive model for cardiac death. Neither λ nor other HRV indices was an independent predictor of AMI recurrence. Among post-AMI patients, increased λ is associated exclusively with increased cardiac mortality risk and its predictive power is independent of clinical risk factors and of other HRV predictors.

BACKGROUND: No reliable precursor of sudden cardiac death is known. METHODS AND RESULTS: Holter electrocardiograms of 34 patients experiencing a cardiac event (event group, 20 deaths) were compared with 191 controls (no event group). The event group included 25 patients with ventricular fibrillation or acute myocardial infarction (AMI), and 9 with cardiac arrest due to complete atrioventricular block. The logarithms were calculated of the moving average of 5 successive values for the low-frequency component (LF), the high-frequency component (HF), and the ratio LF/HF of heart rate variability: ln(LF), ln(HF) and ln(LF/HF). A V-shaped trough appeared in the curve of ln(LF/HF) [sV-trough] or ln(HF) [pV-trough] before such an event in 31 patients in the event group. The V-trough was marked by a small variation lasting 2 h, an abrupt descent lasting 30 min, and a sharp ascent for 40 min. An sV-trough was observed in 22 patients before the onset of ventricular fibrillation or AMI. A pV-trough was observed in all 9 patients before the onset of complete atrioventricular block. In the no event group, an sV-trough and a pV-trough were observed in 10 subjects (5%) and 20 subjects (10%), respectively. The positive predictive accuracy of an sV-trough for ventricular fibrillation or AMI and that of a pV-trough for complete atrioventricular block was 88% and 100%, respectively. CONCLUSIONS: A previously unidentified V-trough of autonomic activity is a potential precursor of lethal events.

Ventricular fibrillation (VF) is known to be the most dangerous cardiac arrhythmia, frequently leading to sudden cardiac death (SCD). During VF, cardiac output drops to nil and, unless the fibrillation is promptly halted, death usually ensues within minutes. While delivering life saving electrical shocks is a method of preventing SCD, it has been recognized that some, though not many, VF episodes are self-terminating, and understanding the mechanism of spontaneous defibrillation might provide newer therapeutic options for treatment of this otherwise fatal arrhythmia. Using the phase statistics approach, recently developed to study financial and physiological time series, here, we reveal the timing characteristics of transient features of ventricular tachyarrhythmia (mostly VF) electrocardiogram (ECG) and find that there are three distinct types of probability density function (PDF) of phase distributions: uniform (UF), concave (CC), and convex (CV). Our data show that VF patients with UF or CC types of PDF have approximately the same probability of survival and nonsurvival, while VF patients with CV type PDF have zero probability of survival, implying that their VF episodes are never self-terminating. Our results suggest that detailed phase statistics of human ECG data may be a key to understanding the mechanism of spontaneous defibrillation of fatal VF.

BACKGROUND: Drugs with I(Kr)-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown. METHODS AND RESULTS: Genetic testing was carried out for long-QT syndrome-related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P<0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS. CONCLUSIONS: dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When I(Kr)-blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.