渡邉 英一

Multiscale entropy (MSE) profiles of heart rate variability (HRV) in patients with atrial fibrillation (AFib) provides clinically useful information for ischemic stroke risk assessment, suggesting that the complex properties characterized by MSE profiles are associated with ischemic stroke risk. However, the meaning of HRV complexity in patients with AFib has not been clearly interpreted, and the physical and mathematical understanding of the relation between HRV dynamics and the ischemic stroke risk is not well established. To gain a deeper insight into HRV dynamics in patients with AFib, and to improve ischemic stroke risk assessment using HRV analysis, we study the HRV characteristics related to MSE profiles, such as the long-range correlation and probability density function. In this study, we analyze the HRV time series of 173 patients with permanent AFib. Our results show that, although HRV time series in patients with AFib exhibit long-range correlation (1/f fluctuations)-as observed in healthy subjects-in a range longer than 90 s, these autocorrelation properties have no significant predictive power for ischemic stroke occurrence. Further, the probability density function structure of the coarse-grained times series at scales greater than 2 s is dominantly associated with ischemic stroke risk. This observation could provide valuable information for improving ischemic stroke risk assessment using HRV analysis.

Implantable cardioverter-defibrillators (ICDs) improve the survival in patients at risk of sudden cardiac death. However, these patients have an ongoing risk of sudden incapacitation that may cause harm to individuals and others when driving. Considerable disagreement exists about whether and when these patients should be allowed to resume driving after ICD therapies. This information is critical for the management decisions to avoid future potentially lethal incidents and unnecessary restrictions for ICD patients. The cardiac implantable device committee of the Japanese Heart Rhythm Society reassessed the risk of driving for ICD patients based on the literature and domestic data. We reviewed the driving restrictions of ICD patients in various regions and here present updated Japanese driving restrictions.

BACKGROUND: A modestly elevated circulating D-dimer level may be relevant to coronary artery disease (CAD), but its prognostic value, both independently and in combination with estimated glomerular filtration rate (eGFR), for long-term death has not been fully evaluated in stable CAD patients.Methods and Results:Baseline plasma D-dimer levels and eGFR were measured in 1,341 outpatients (mean age: 65 years) with prior myocardial infarction (MI), coronary revascularization, and/or angiographic evidence of a significant stenosis (>50%) for at least one of the major coronary arteries. Among these patients, 43% had prior MI, 47% had prior coronary revascularization, 41% had multivessel CAD, 14% had paroxysmal or persistent atrial fibrillation, 32% had diabetes, and 32% had chronic kidney disease (eGFR <60 mL/min/1.73 m2). D-dimer levels weakly correlated with eGFR (r=-0.25; P<0.0001). During a mean follow-up period of 73 months, there were 124 deaths, including 61 cardiovascular deaths. Multivariate Cox regression analysis identified D-dimer levels (P=0.001) and eGFR (P=0.006) as independent predictors of all-cause death. Adding both D-dimer and eGFR to a baseline model with established risk factors improved the net reclassification (P<0.005) and integrated discrimination improvement (P<0.05) greater than that of any single biomarker or baseline model alone. CONCLUSIONS: The combinatorial value of assessing D-dimer levels and eGFR may provide useful insight regarding stable CAD patients' long-term risk stratification.

Multifractal analysis of cardiovascular variability series is an effective tool for the characterization of pathological states associated with congestive heart failure (CHF). Consequently, variations of heartbeat scaling properties have been associated with the dynamical balancing of nonlinear sympathetic/vagal activity. Nevertheless, whether vagal dynamics has multifractal properties yet alone is currently unknown. In this study, we answer this question by conducting multifractal analysis through wavelet leader-based multiscale representations of instantaneous series of vagal activity as estimated from inhomogeneous point process models. Experimental tests were performed on data gathered from 57 CHF patients, aiming to investigate the automatic recognition accuracy in predicting survivor and non-survivor patients after a 4 years follow up. Results clearly indicate that, on both CHF groups, the instantaneous vagal activity displays power-law scaling for a large range of scales, from ≃ 0.5s to ≃ 100s. Using standard SVM algorithms, this information also allows for a prediction of mortality at a single-subject level with an accuracy of 72.72%.

PURPOSE: Patients with implantable cardioverter defibrillators (ICDs) have an ongoing risk of sudden incapacitation that may cause traffic accidents. However, there are limited data on the magnitude of this risk after inappropriate ICD therapies. We studied the rate of syncope associated with inappropriate ICD therapies to provide a scientific basis for formulating driving restrictions. METHODS: Inappropriate ICD therapy event data between 1997 and 2014 from 50 Japanese institutions were analyzed retrospectively. The annual risk of harm (RH) to others posed by a driver with an ICD was calculated for private driving habits. We used a commonly employed annual RH to others of 5 in 100,000 (0.005%) as an acceptable risk threshold. RESULTS: Of the 4089 patients, 772 inappropriate ICD therapies occurred in 417 patients (age 61 ± 15 years, 74% male, and 65% secondary prevention). Patients experiencing inappropriate therapies had a mean number of 1.8 ± 1.5 therapy episodes during a median follow-up period of 3.9 years. No significant differences were found in the age, sex, or number of inappropriate therapies between patients receiving ICDs for primary or secondary prevention. Only three patients (0.7%) experienced syncope associated with inappropriate therapies. The maximum annual RH to others after the first therapy in primary and secondary prevention patients was calculated to be 0.11 in 100,000 and 0.12 in 100,000, respectively. CONCLUSIONS: We found that the annual RH from driving was far below the commonly cited acceptable risk threshold. Our data provide useful information to supplement current recommendations on driving restrictions in ICD patients with private driving habits.

Atrial remodeling is considered to be any persistent change in atrial structure or function, and is responsible for the development and perpetuation of atrial fibrillation (AF). Oxidative stress and intracellular pH regulation may also be linked to AF; however it remains unclear whether eicosapentaenoic acid (EPA) or statins have beneficial therapeutic effects. The aim of the present study was to investigate the effects of EPA and pitavastatin on the electrophysiology of and gene expressions in mice with rapidly-paced atria. Mice were treated with EPA (10 mg/g/day) or pitavastatin (30 ng/g/day) for 6 weeks, following which AF was simulated by 8-h atrial pacing at 1,800 bpm. The atrial electrophysiological properties and the expression of cardiac genes, potassium voltage-gated channel subfamily A member 5 (Kcna5), Kcn subfamily D member 2 (Kcnd2), Kv channel-interacting protein 2 (KChIP2), solute carrier family 9 member A1, thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI) were examined using reverse transcription-quantitative polymerase chain reaction. In control mice, significant atrial electrical remodeling was observed (P<0.05); however, treatment with either EPA or pitavastatin ameliorated these electrophysiological changes (P>0.05). mRNA levels of Kcnd2, KChIP2 and Kcna5 were significantly upregulated in control mice (P<0.05), whereas treatment with EPA or pitavastatin attenuated this upregulation (P>0.05). Administration of pitavastatin significantly reduced the downregulation of both TFPI and TM (P<0.05). EPA treatment attenuated the TFPI downregulation compared with control mice (P>0.05), however no significant effect on TM expression was observed. In addition, both EPA (P>0.05) and pitavastatin (P<0.05) suppressed the overexpression of endothelial nitric oxide synthase. This was also exhibited in Ras-related C3 botulinum toxin substrate 1 genes (P<0.01 for both treatments). In conclusion, the results of the present study suggested that EPA and pitavastatin are able to prevent atrial electrical remodeling, thrombotic states and oxidative stress in rapidly-paced murine atria.

Aims: Cyclic variation of heart rate (CVHR) associated with sleep-disordered breathing is thought to reflect cardiac autonomic responses to apnoeic/hypoxic stress. We examined whether blunted CVHR observed in ambulatory ECG could predict the mortality risk. Methods and results: CVHR in night-time Holter ECG was detected by an automated algorithm, and the prognostic relationships of the frequency (FCV) and amplitude (ACV) of CVHR were examined in 717 patients after myocardial infarction (post-MI 1, 6% mortality, median follow-up 25 months). The predictive power was prospectively validated in three independent cohorts: a second group of 220 post-MI patients (post-MI 2, 25.5% mortality, follow-up 45 months); 299 patients with end-stage renal disease on chronic haemodialysis (ESRD, 28.1% mortality, follow-up 85 months); and 100 patients with chronic heart failure (CHF, 35% mortality, follow-up 38 months). Although CVHR was observed in ≥96% of the patients in all cohorts, FCV did not predict mortality in any cohort. In contrast, decreased ACV was a powerful predictor of mortality in the post-MI 1 cohort (hazard ratio [95% CI] per 1 ln [ms] decrement, 2.9 [2.2-3.7], P < 0.001). This prognostic relationship was validated in the post-MI 2 (1.8 [1.4-2.2], P < 0.001), ESRD (1.5 [1.3-1.8], P < 0.001), and CHF (1.4 [1.1-1.8], P = 0.02) cohorts. The prognostic value of ACV was independent of age, gender, diabetes, β-blocker therapy, left ventricular ejection fraction, sleep-time mean R-R interval, and FCV. Conclusion: Blunted CVHR detected by decreased ACV in a night-time Holter ECG predicts increased mortality risk in post-MI, ESRD, and CHF patients.

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.

To evaluate long-range cross-correlated behavior observed in bivariate time series, detrended cross-correlation analysis (DCCA) was proposed. In the DCCA, trends embedded in each time series are eliminated via piecewise least-squares polynomial fitting in the same way as the detrended fluctuation analysis (DFA). In this paper, as an improved variant of DCCA, we propose a DCCA method using the Savitzky-Golay detrending filters and its fast implementation algorithm. In addition, as an application of our method, we analyze the cardiorespiratory interaction.

Additional risk stratification may provide more aggressive and focalized preventive treatment to high-risk hypertensive patients according to the Japanese hypertension guidelines. We prospectively investigated the predictive value of high-sensitivity troponin I (hsTnI), both independently and in combination with N-terminal pro-B-type natriuretic peptide (NT-proBNP), for incident heart failure (HF) in high-risk hypertensive patients with preserved left ventricular ejection fraction (LVEF). Baseline hsTnI and NT-proBNP levels and echocardiography data were obtained for 493 Japanese hypertensive outpatients (mean age, 68.5 years) with LVEF ≥ 50%, no symptomatic HF, and at least one of the following comorbidities: stage 3-4 chronic kidney disease, diabetes mellitus, and stable coronary artery disease. During a mean follow-up period of 86.1 months, 44 HF admissions occurred, including 31 for HF with preserved ejection fraction (HFpEF) and 13 for HF with reduced ejection fraction (HFrEF; LVEF <50%). Both hsTnI (p < 0.01) and NT-proBNP (p < 0.005) levels were significant independent predictors of HF admission. Furthermore, when the patients were stratified into 4 groups according to increased hsTnI (≥highest tertile value of 10.6 pg/ml) and/or increased NT-proBNP (≥highest tertile value of 239.7 pg/ml), the adjusted relative risks for patients with increased levels of both biomarkers versus neither biomarker were 13.5 for HF admission (p < 0.0001), 9.45 for HFpEF (p = 0.0009), and 23.2 for HFrEF (p = 0.003). Finally, the combined use of hsTnI and NT-proBNP enhanced the C-index (p < 0.05), net reclassification improvement (p = 0.0001), and integrated discrimination improvement (p < 0.05) to a greater extent than that of any single biomarker. The combination of hsTnI and NT-proBNP, which are individually independently predictive of HF admission, could improve predictions of incident HF in high-risk hypertensive patients but could not predict future HF phenotypes.

BACKGROUND: Takotsubo cardiomyopathy (TC) is a myopathy triggered by severe stressful events. However, little is known about the determinants of in-hospital outcomes. We prospectively determined the effect of different triggers on the prognosis of TC. METHODS AND RESULTS: We enrolled patients who were admitted for suspected acute coronary syndrome (ACS) from January 2008 to December 2015. TC was diagnosed according to the Mayo Clinic diagnosis criteria. The outcome was in-hospital death. Among 1861 consecutive patients with suspected ACS, 82 (4.4%) patients were diagnosed with TC. There were 43 patients (52%) with physical triggers (Physical), 26 (31%) with emotional triggers, and 13 (17%) with no identifiable triggers. The latter two groups were combined and categorized as the Non-physical trigger group. Compared with non-physical triggered TC, patients with physical triggered TC were more likely to have a malignancy (p=0.008), lower blood pressure (p=0.001), lower hemoglobin (p<0.001), higher serum creatinine (p<0.001) and higher norepinephrine levels (p=0.007). During a mean hospital stay of 16±12days, 9 (20.9%) of the Physical and 1 (2.6%) of the Non-physical patients died in-hospital (log-rank p=0.007). After adjusting for the age, gender, trigger, malignancy, and hemoglobin level, being male (hazard ratio 11.9, 95% confidence interval, 2.43-58.5, p=0.002) and having a physical trigger (14.7, 1.19-166, p=0.03) were associated with in-hospital mortality. CONCLUSION: There was a significant difference in in-hospital mortality depending on the trigger type in TC. Being male and having a physical trigger were independent risk factors of in-hospital mortality from TC.

Whether trough-phase rivaroxaban concentrations provide sufficient anticoagulation needs more study. We evaluated levels of coagulation activation markers in the trough concentration phase in nonvalvular atrial fibrillation (NVAF) patients, and the correlation between these markers and rivaroxaban concentration. Fifty-five Japanese NVAF patients received 24-week rivaroxaban treatment of either 15 or 10 mg once-daily in the morning. Of these, 26 patients had no history of anticoagulant therapy (naive group) and 29 had switched from warfarin (warfarin group). D-dimer and prothrombin fragment 1 + 2 (F1 + 2) levels, and protein C activities were measured at 0 (baseline), 12 and 24 weeks of rivaroxaban treatment just before the patient's regular dosing time (trough phase). For 49 patients, D-dimer, F1 + 2, and rivaroxaban concentrations were also measured twice between 28 and 32 weeks of rivaroxaban treatment at non-trough times to achieve a range of drug concentrations for correlation analysis. For the naive group, D-dimer and F1 + 2 levels were significantly reduced (p < 0.01) from baseline at 12 and 24 weeks. For the warfarin group, these values were unchanged for D-dimer but significantly increased (p < 0.01) for F1 + 2. Protein C activity was unchanged in the naive group and was increased (p < 0.01) in the warfarin group. Prothrombin time (r = 0.92, p < 0.0001) and activated partial thromboplastin time (r = 0.54, p < 0.0001) correlated with rivaroxaban concentration, but not D-dimer and F1 + 2 levels. In conclusion, rivaroxaban in the trough phase is comparable to warfarin in reducing D-dimer levels. Although trough level rivaroxaban suppresses F1 + 2 less than warfarin, the higher activities of protein C with rivaroxaban treatment compared to warfarin treatment may counterbalance this. Lack of correlation between rivaroxaban concentration and D-dimer and F1 + 2 levels suggests that trough concentrations of rivaroxaban reduce their concentrations as effectively as higher levels do.

BACKGROUND: Sleep-disordered breathing, particularly central sleep apnea (CSA), is highly prevalent in heart failure (HF) and an independent prognostic marker. We assessed the hypothesis that an increased hypoxemic burden during sleep may have greater prognostic value than the frequency of apneic and hypopneic episodes. METHODS AND RESULTS: We prospectively conducted overnight cardiorespiratory polygraphy on consecutive HF patients referred to our hospital from 2008 to 2011. We studied CSA defined by an apnea-hypopnea index (AHI) of ≥5 events/h with >75% of all events being central in origin. We determined the AHI, proportion of the sleep time with SpO2 <90% (T90%), and proportion of the recording time that 4% desaturation events occurred (4%POD). We studied 112 HF patients with either systolic or diastolic dysfunction. During a follow-up period of 37 ± 25 months, 32 patients (29%) died. Nonsurvivors had a higher 4%POD compared with survivors (11 ± 6.4% vs 19 ± 13%; P = .001), but did not differ significantly from survivors regarding AHI and T90%. An adjusted logistic regression analysis revealed that the 4%POD was the best independent predictor of mortality. CONCLUSIONS: The 4%POD, a novel metric for the nocturnal hypoxemic burden, is an independent prognostic marker in HF patients affected by CSA.

OBJECTIVES: The number of elderly patients with hypertension has been steadily increasing. However, there are limited data on the safety and efficacy of the new angiotensin type 1 receptor blocker (ARB) azilsartan in elderly patients with hypertension. We investigated the clinical efficacy and safety of azilsartan in this population. METHODS: The study population comprised 56 ambulatory patients with essential hypertension. We evaluated the reduction in blood pressure and safety after 12 weeks of treatment with azilsartan in 29 hypertensive patients ≥65 years of age (aged group) in comparison with the findings in 27 patients <65 years of age (non-aged group). RESULTS: Systolic blood pressure in the aged group declined significantly from 155 ± 18 mmHg at baseline to 138 ± 11 mmHg after 12 weeks of treatment with azilsartan, and that in the non-aged group also declined significantly from 152 ± 20 mmHg at baseline to 142 ± 13 mmHg after 12 weeks of treatment with azilsartan. There were no significant differences in the magnitude of change in blood pressures from pre-treatment to post-treatment with azilsartan between the non-aged and aged groups. There were no changes in clinical laboratory findings, including serum levels of creatinine, potassium, lipids, and other metabolic variables, after 12 weeks of treatment with azilsartan in both groups. CONCLUSIONS: Our findings suggest that azilsartan is effective in lowering blood pressure in elderly patients and may be safe. Therefore, azilsartan could be a valuable option for treating hypertension in elderly and non-elderly patients.

OBJECTIVE: The aim of this study was to investigate the significance of late potential (LP) after percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS). METHOD: 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. RESULTS: The body mass index, serum creatinine, and creatine phosphokinase-MB were higher in the LP-positive group than in the LP-negative group (p < 0.05). 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; p < 0.01). CONCLUSION: Positive LP in patients with ACS after PCI may predict re-hospitalization.

General uroflowmetry method involves the risk of nosocomial infections or time and effort of the recording. Medical institutions, therefore, need to measure voided volume simply and hygienically. Multiple cylindrical model that can estimate the fluid flow rate from the photographed image using camera has been proposed in an earlier study. This study implemented a flow rate estimation by using a general-purpose camera system (Raspberry Pi Camera Module) and the multiple cylindrical model. However, large amounts of noise in extracting liquid region are generated by the variation of the illumination when performing measurements in the bathroom. So the estimation error gets very large. In other words, the specifications of the previous study's camera setup regarding the shutter type and the frame rate was too strict. In this study, we relax the specifications to achieve a flow rate estimation using a general-purpose camera. In order to determine the appropriate approximate curve, we propose a binarizing method using background subtraction at each scanning row and a curve approximation method using RANSAC. Finally, by evaluating the estimation accuracy of our experiment and by comparing it with the earlier study's results, we show the effectiveness of our proposed method for flow rate estimation.

For the assessment of autonomic nervous system activity based on heart rate variability (HRV) analysis, characteristics of high-frequency (HF; 0.15 to 0.4 Hz) and low-frequency (LF; 0.04 to 0.15 Hz) components have been widely employed. HF and LF band powers quantified by power spectral analysis have most commonly been used in the conventional studies; the physiological significance of these measures has also been extensively studied. However, nonlinear characteristics of HF and LF components have not been well established. In this paper, we investigated nonlinear properties of HF and LF components in 122 healthy subjects and 108 patients with congestive heart failure (CHF). By analyzing bandpass-filtered time series of HRV corresponding to HF and LF components, it is shown that amplitude variability of HF and LF components displays long-range correlation, which cannot be explained by linear HRV properties. Compared with the age-matched healthy control group, the CHF patients showed significantly decreased long range correlation of HF component amplitude variability. These findings suggest that nonlinear properties of HF and LF components provides some complementary information on HRV dynamics.

BACKGROUND: The proportion of patients with atrial fibrillation (AF) treated with anticoagulation varies from country to country. In Japan, little is known about regional differences in frequency of warfarin use or prognosis among patients with non-valvular AF (NVAF). METHODS AND RESULTS: In J-RHYTHM Registry, the number of patients recruited from each of 10 geographic regions of Japan was based on region population density. A total of 7,406 NVAF patients were followed up prospectively for 2 years. At baseline, significant differences in various clinical characteristics including age, sex, type of AF, comorbidity, and CHADS2score, were detected among the regions. The highest mean CHADS2score was recorded in Shikoku. Frequency of warfarin use differed between the regions (P<0.001), with lower frequencies observed in Hokkaido and Shikoku. Baseline prothrombin time international normalized ratio differed slightly but significantly between the regions (P<0.05). On univariate analysis, frequency of thromboembolic events differed among the regions (P<0.001), with the highest rate seen in Shikoku. An inverse correlation was detected between frequency of thromboembolic and of major hemorrhagic events (P=0.062). On multivariate analysis, region emerged as an independent risk for thromboembolism. CONCLUSIONS: Thromboembolic risk, frequency of warfarin use, and intensity and quality of warfarin treatment differed significantly between geographic regions of Japan. Region was found to be an independent predictor of thromboembolic events. (Circ J 2016; 80: 1548-1555).

New oral anticoagulants (NOACs) are now clinically available. However, few studies have demonstrated which patients with non-valvular atrial fibrillation (NVAF) actually receive NOACs in a clinical setting. We analyzed 182 NVAF patients who received oral anticoagulants. Clinical backgrounds and the risk of stroke, systemic embolism, and bleeding associated with oral anticoagulants were investigated. Seventy-three (40 %) patients were treated with NOACs and 109 (60 %) patients were treated with warfarin. A significantly lower mean number of bleeding risk factors was observed among the patients treated with NOACs than among those treated with warfarin (P = 0.010). Of the bleeding risk factors, NOACs were significantly less frequently prescribed in patients with a bleeding history and elderly subjects (>65 years) than in those who received warfarin (P < 0.001 and P = 0.029). A multivariate logistic regression analysis revealed that CHF and bleeding history were independently and significantly associated with the administration of NOACs (P = 0.047 and P = 0.003). The rate of a history of intracranial hemorrhage was comparable between the patients treated with NOACs and those treated with warfarin (P = 1.000). Significantly lower rates of a history of gastrointestinal and other minor bleeding were observed in the patients who received NOACs versus those who received warfarin (P = 0.001 and P = 0.026). NOACs were less frequently prescribed in patients with a history of bleeding, especially those with a history of gastrointestinal bleeding in a clinical setting.

BACKGROUND: Concomitant use of vitamin K antagonist (VKA) and aspirin (ASA) is becoming increasingly prevalent among atrial fibrillation (AF) patients. We quantified the net clinical benefit of adding ASA to a VKA using nationwide prospective AF registry data. METHODS: We studied 6074 patients (VKA monotherapy: 83% and VKA+ASA: 17%) between January 2009 and July 2009, and followed them for a mean follow-up period of 2years. The risk of strokes and bleeding was calculated by the CHA2DS2-VASc and HAS-BLED scores. The net clinical benefit was defined as the annual rate of ischemic strokes and systemic emboli prevented by VKAs minus intracranial hemorrhages attributable to the VKA+ASA, multiplied by an impact weight of 1.5. RESULTS: Patients on a VKA+ASA were older with more medical comorbidities than those on VKA alone. Using VKA monotherapy as a reference, higher major bleeding rates and all-cause death were evident in those on VKA+ASA. The net clinical benefit of VKA+ASA for the overall cohort was -0.1%/year (95% confidence interval, -0.74% to 0.46%). There was a trend toward a negative net clinical benefit from VKA+ASA in patients with a CHA2DS2-VASc≥2 and HAS-BLED≤2 (-1.17%/year). The VKA+ASA yielded a positive net clinical benefit in patients with a CHA2DS2-VASc≥2 and HAS-BLED≥3 (1.16%/year). The result patterns were relatively constant using impact weight of 1.0 and 2.0. CONCLUSIONS: Our estimates of the net clinical benefit can provide a useful anchoring point for adding ASA to VKA in patients with AF.

BACKGROUND: Both Takotsubo cardiomyopathy (TTC) and reverse TTC (r-TTC) are characterized by reversible regional wall motion abnormalities of the heart unrelated to coronary artery pathology. It remains unclear whether and/or how r-TTC differs from TTC. Subarachnoid hemorrhage (SAH) is occasionally causative of TTC/r-TTC, and this study was conducted to detect possible differences between TTC and r-TTC associated with SAH. METHODS: A single-center retrospective study was conducted on 328 consecutive SAH patients. They routinely underwent transthoracic echocardiography (TTE), ECG, and measurements of plasma catecholamines and other cardiac biomarkers within 24 h of admission. Demographic, echocardiographic, electrocardiographic and neurochemical profiles were compared between patients with TTC and r-TTC. The diagnosis of TTC/r-TTC was based on the revised Mayo Clinic Criteria. RESULTS: Data of 21 SAH-induced TTC and 10 SAH-induced r-TTC patients admitted between January 2009 and December 2014 were analyzed. The patients with r-TTC were significantly younger than those with TTC (51.8 ± 10.9 vs. 63.5 ± 14.4 years, p = 0.04). The former exhibited significantly higher plasma epinephrine levels than the latter (809 ± 710 vs. 380 ± 391 pg/mL, p = 0.04). Plasma norepinephrine levels did not differ significantly (2421 ± 1374 vs. 1724 ± 1591 pg/mL, p = 0.25). No significant differences were observed in other demographic/physiologic variables, echocardiographic parameters, frequency of ECG abnormalities, and 90-day mortality. Moreover, none of the patients who underwent a follow-up TTE exhibited morphologic change from one type to the other. CONCLUSIONS: The pathomechanisms in TTC and r-TTC may not be identical: however, distinguishing the two conditions may not have great importance from the standpoint of clinical management and prognostication.

抗不整脈薬の単回経口投与による薬理学的除細動は，薬物の長期投与による副作用を回避し，心房細動（AF）の症状やリスクを早期に軽減する目的で行われる．われわれは，日本人のAF患者においてフレカイニドとプロパフェノンの単回経口投与の有効性と安全性を検討した．発作性AF患者29例をフレカイニド100mg（F群，n＝15；65±15歳），またはプロパフェノン150mg（P群, n＝14；61±12歳）にランダム化して単回経口投与を行い，投与後120分間の除細動成功率を比較検討した．患者背景は両群間で差を認めず，両群とも経時的な心拍数，血圧，QRS幅，QTc間隔の変動を認めなかった．除細動成功例はF群で3例（20％），P群で7例（50％）（p値＝0.09），洞調律回復までの時間はF群で70±17分，P群で77±34分であった（p値＝0.74）．F群で（非）通常型心房粗動（心拍数144/分）を1例認めた．F群の有効性が低かったものの両群間で有意差を認めず，日本人のAF患者に対して，本研究の薬物投与量ではほぼ安全に単回経口投与が行えることが示された．

Inpatients of circulatory system disease must manage their urine volume every day since they have low ability to control fluid balance inside their bodies. In most hospitals, measuring cups are used which lead to nosocomial infection. Our study propose a new method of urine volume estimation without using a cup. We propose multiple cylindrical model to estimate the amount of liquid volume from images taken by a monocular camera. This model is based on the idea of calculating the total volume of cylinder extracted from each image. First, images of liquid simulating male urination are binarized to derive features for the model. Each volume of cylinder is calculated by the initial velocity and diameter of liquid in each image. We conducted experiments to evaluate the model. As a result, we suggest that this model could be a new way of urine volume management for inpatients.

Heart rate variability (HRV) is a noninvasive methodology for evaluating the autonomic nervous system modulation of the sinoatrial node and to identify patients at risk of cardiac disorders. The contemporary therapeutic use for the HRV analysis is for risk stratification in patients with post-myocardial infarction or heart failure who are prone to have arrhythmic death and who would benefit from implantable cardioverter-defibrillators (ICDs). Although multiple HRV measurements have been developed to achieve a better risk stratification, the HRV measurements have been rarely tested to see whether they harbor a significant power to serve as a practical risk predictor. To date, the only reliable metric to predict the benefit from an ICD is a severely reduced ejection fraction however, the predictive value of the ejection fraction is relatively low. Because of the high negative predictive value of the HRV, a combination with the ejection fraction may be helpful to identify candidates who are unlikely to benefit from ICD therapy. A more sophisticated risk approach that combines the HRV and other known clinical measures should be developed to provide accurate estimates of the risk to allow patients to make informed treatment decisions. Another requirement is to explore the novel HRV measurements for atrial fibrillation. The prevalence of atrial fibrillation rapidly increases among the aging population and is independently associated with a higher risk of ischemic strokes and excess mortality. The HRV measurements specific for atrial fibrillation may facilitate the risk stratification in such a high-risk population.

The available epidemiological and clinical data implicate increased sympathetic nervous system activity in increased cardiovascular morbidity and mortality and show that it has strong predictive power for mortality and cardiovascular events. Analysis of heart rate variability (HRV) has been widely used as a noninvasive assessment tool for autonomic nervous system function, and results show that reduced and/or abnormal HRV is associated with an increased risk of mortality in cardiac patients such as patients after acute myocardial infarction and patients with congestive heart failure. However, most indices derived from HRV primarily reflect vagal function. In contrast, few indices have been suggested as markers of sympathetic nervous system activity. This chapter reviews characteristics of HRV that have been proposed as potential markers of cardiac sympathetic activity, such as (in the frequency domain) low-frequency (LF) power, short-term scaling exponent, and non-Gaussianity index. While there is no widely accepted and well-tested HRV-based index of cardiac sympathetic activity, we discuss the key issues for the assessment of cardiac sympathetic activity based on HRV analysis.

<p>Long-range correlations have been observed in a wide variety of biosignal time series. It has been demonstrated that its alteration is associated with a disease state and higher mortality. Thus, fast and reliable characterization of long-range correlations is an important task. Among scaling analysismethods, it has been demonstrated that higher-order centered detrending moving average (DMA) analysis has good performance. However, a straightforward implementation of higher-order DMA requires a very long computational time. To solve this issue, we introduce a fast algorithm for higher order DMA. Our algorithm can significantly reduce computational cost; the computational time of our algorithm is approximately proportional to the data length, although that of the conventional algorithm is proportional to the square of the data length. Through the analysis of artificial and heart rate variability time series, we discuss possible applications of higher order DMA.</p>

<p>Power spectral estimation of heart rate variability (HRV) has been widely employed to assess autonomic nervous system function. Among Power spectral-based indices, high-frequency (HF; 0.15 to 0.4 Hz) and low-frequency (LF; 0.04 to 0.15 Hz) band powers have most commonly been used; the physiological significance of these indices has also been extensively studied. However, nonlinear properties of HF and LF components have not been well understood. In this study, we investigated nonlinearity of HF and LF components in 122 healthy subjects and 108 patients with congestive heart failure (CHF). By analyzing bandpass-filtered time series of HRV corresponding to HF and LF components, it is shown that the amplitude modulations display long-range correlation indicating nonlinearity. Compared with the age-matched healthy controls, the CHF patients showed significantly decreased long-range correlation of HF amplitude modulation. Our findings suggest that nonlinearity of HF and LF components provides some complementary information on HRV dynamics.</p>

<p>As Japan is facing a super-aged society, growing medical expenses and doctor shortage have become major public health problems. To cope with these problems, it is important to forecast future demand of medical services and supplies. To provide an insight into such problems, we here investigate future demand for cardiac implantable electrical devices, such as pacemaker (PM) and implantable cardioverter defibrillator (ICD). In this study, based on the analysis of past records of annual number of PM and ICD implantation from 2006 to 2014 in Japan, we build a predictive model to forecast the future number of PM and ICD implantation. In this model, age and gender composition rates of population are assumed to be explanatory variables. As an application of this model, we estimate the future demand of PM and ICD devices in each prefecture in Japan until 2040, and discuss regional differences.</p>

AIMS: Premature ventricular complexes (PVCs) originating from the right ventricular outflow tract (RVOT) may occasionally trigger monomorphic ventricular tachycardia (MVT), polymorphic ventricular tachycardia (PVT), or ventricular fibrillation (VF). We examined whether an analysis of the ventricular repolarization instability could differentiate PVT/VF triggered by RVOT-PVCs from benign RVOT-PVCs or MVT. METHODS: We evaluated the ventricular repolarization instability as assessed by the beat-to-beat T-wave amplitude variability (TAV) using Holter recordings in patients with RVOT-PVCs but with no structural heart disease. We determined the prematurity index, defined as the ratio of the coupling interval of the first ventricular tachycardia (VT) beat or isolated PVC to the preceding R-R interval just before the VT or isolated PVC in the Holter recordings. The study patients were classified into RVOT-PVCs/MVT (n = 33) and PVT/VF (n = 10). RESULTS: The two groups did not differ with respect to the age, sex, and left ventricular ejection fraction. There was no significant difference in the prematurity index between the two groups (RVOT-PVCs/MVT 0.66 ± 0.16 vs. PVT/VF 0.61 ± 0.13, P = 0.60). The patients with PVT/VF had a significantly larger maximum TAV than those with RVOT-PVCs/MVT (31 ± 13 vs. 68 ± 40 µV, P < 0.001). Patients with a higher than median value of the TAV (33 µV) were at increased risk of PVT/VF vs. those with a lower than median value, after adjusting for the age and sex [9.25 (95% confidence interval: 1.27-19.2); P = 0.03]. CONCLUSIONS: The TAV analysis is a useful measure to identify the subset of usually benign RVOT-PVC/MVT patients prone to PVT/VF.

BACKGROUND: Cardiac sarcoidosis (CS) generates myocardial scar and arrhythmogenic substrate. CS diagnosis according to the Japanese Ministry of Health and Welfare guidelines relies, among others, on cardiac magnetic resonance imaging with late gadolinium enhancement (CMR-LGE). However, access to CMR-LGE is limited. The electrocardiography-based Selvester QRS score has been validated for identifying myocardial scar in ischemic/nonischemic cardiomyopathy, but its efficacy has not been tested to evaluate CS. OBJECTIVE: The purpose of this study was to examine whether the QRS score can be applied to CS. METHODS: CS-associated myocardial scar was assessed by both CMR-LGE and QRS scoring in patients with extra-CS (n = 59). RESULTS: Of 59 patients, 35 (59%) were diagnosed with CS according to the Japanese Ministry of Health and Welfare guidelines. QRS-estimated scar mass positively correlated with that quantified by CMR-LGE (signal intensity ≥2SD above the reference; r = 0.68; P < .001). Receiver operating characteristic curves demonstrated optimal cutoffs of 9% CMR-LGE scar and 3-point QRS score to identify patients with CS. The areas under the curves of CMR-LGE and the QRS score were not significantly different (0.83 and 0.78, respectively; P = .27); both methods demonstrated similar diagnostic performance. A QRS score of ≥3 led to a higher incidence of CS-associated adverse events (death/fatal arrhythmia/heart failure hospitalization) than did a QRS score of <3 (35 ± 21 months of follow-up; P = .01). QRS score was an independent predictor of risk in multivariate analysis (P = .03). CONCLUSION: The Selvester QRS scoring estimates CS-associated myocardial damage and identifies patients with CS equally well as CMR-LGE. A higher QRS score is also associated with an increased risk of life-threatening events in CS, indicating its potential use as a risk predictor.

INTRODUCTION: Recently, direct-acting oral anticoagulants (DOACs) have been introduced, with increasing use in patients with non-valvular atrial fibrillation (NVAF). However, warfarin continues to be widely used and the benefits and risks of warfarin in NVAF patients warrant closer inspection. MATERIALS AND METHODS: Thromboembolism, major hemorrhage, and total and cardiovascular mortalities were analyzed in 7,406 NVAF patients in the J-RHYTHM Registry from January to July 2009, prior to DOAC introduction. Propensity score matching analysis was performed to reduce the differences in clinical characteristics between non-anticoagulant (n=1002) and warfarin (n=6404) cohorts to reassess warfarin outcomes over 2years. RESULTS: The incidence of thromboembolism was significantly greater in the non-anticoagulant cohort (3.0%) than in the warfarin cohort (1.5%, P<0.001) with less frequent major hemorrhage in the non-anticoagulant cohort (0.8%) than in the warfarin cohort (2.1%, P=0.009). Using propensity score matching, new subsets (n=896 each) were obtained, with matching of the clinical characteristics between warfarin and non-anticoagulant subsets. The warfarin subset had lower risk factors compared with the total warfarin cohort. The incidence of thromboembolism was higher in the non-anticoagulant subset (2.9%) than in the warfarin subset (0.7%, P<0.001). However, major hemorrhage was not significantly different between the two subsets. CONCLUSIONS: Although warfarin was associated with a significantly higher incidence of hemorrhage in the unmatched cohorts, propensity score matching revealed that warfarin reduced thromboembolism without a significant increase in hemorrhage in the matched subsets with lower risks. Propensity score matching reduced selection bias and provided rational comparisons although it had indwelling limitations.

Urodynamics measurement tools in practical use carry the risk of nosocomial infection and invasiveness. Our study proposes a new method for urinary flow estimation. We propose multiple cylindrical model to estimate the amount of liquid volume from images taken by a monocular camera. This model is based on the idea of calculating the total volume of cylinder extracted from each image. First, images of liquid simulating male urination are binarized to derive features for the model. Each volume of cylinder is calculated by the initial velocity and diameter of liquid in each image. We conducted experiments to evaluate the model by comparing our estimated volume and flow rate to the data acquired from uroflowmeter in practical use. As a result, estimation was within the accuracy of ±10% which is enough accuracy of actual uroflowmeter being used in Japanese hospitals for practical use.

BACKGROUND AND PURPOSE: Many patients with atrial fibrillation (AF) and coronary artery stent deployment are given both antiplatelet drug and warfarin. Little information is available as to the relationship between the antithrombotic therapies in the late phase after stenting and the clinical outcomes of these patients. We examined the clinical outcomes of AF patients 12 months after coronary artery stenting. METHODS: We retrospectively examined 146 patients and classified them into three groups according to the antithrombotic therapies [dual antiplatelet therapy (DAPT), single antiplatelet therapy (SAPT) plus warfarin, and DAPT plus warfarin] 12 months after stenting. We defined the primary endpoint as Thrombolysis in Myocardial Infarction major bleeding and the secondary endpoint as a composite of adverse events (CAE: all-cause death, nonfatal myocardial infarction, intracranial bleeding, and cerebral infarction). RESULTS: During a median follow-up of 37 months, major bleeding and CAE were observed in 14 (9.6%) and 46 (31.5%) patients, respectively. DAPT plus warfarin was an independent risk factor for major bleeding in a multivariate Cox hazard regression model after adjustment for age, gender, and the type of AF (hazard ratio: 4.20; 95% confidence interval: 1.13-17.27; p=0.033). No significant clinical variables were found for CAE. CONCLUSIONS: Prolonged use of DAPT with warfarin significantly increases the risk of major bleeding in AF patients after coronary artery stenting. Individualized antithrombotic treatment is required in these patients to prevent major bleeding.

Multiscale analysis of human heartbeat dynamics has been proved effective in characterizeing cardiovascular control physiology in health and disease. However, estimation of multiscale properties can be affected by the interpolation procedure used to preprocess the unevenly sampled R-R intervals derived from the ECG. To this extent, in this study we propose the estimation of wavelet coefficients and wavelet leaders on the output of inhomogeneous point process models of heartbeat dynamics. The RR interval series is modeled using probability density functions (pdfs) characterizing and predicting the time until the next heartbeat event occurs, as a linear function of the past history. Multiscale analysis is then applied to the pdfs' instantaneous first order moment. The proposed approach is tested on experimental data gathered from 57 congestive heart failure (CHF) patients by evaluating the recognition accuracy in predicting survivor and non-survivor patients, and by comparing performances from the informative point-process based interpolation and non-informative spline-based interpolation. Results demonstrate that multiscale analysis of point-process high-resolution representations achieves the highest prediction accuracy of 65.45%, proving our method as a promising tool to assess risk prediction in CHF patients.

Non-Gaussianity of heart rate variability (HRV) has been reported to be a predictor of mortality in patients with chronic heart failure (CHF) and in patients after acute myocardial infarction. In those studies, non-Gaussianity index observed at the coarse graining scale of 25s was an independent significant predictor of mortality. To explain the physiological mechanism generating such non-Gaussianity, it has been suggested that non-Gaussian behavior of HRV is related to sympathetic overdrive. However, no correlation between the non-Gaussianity index and conventional frequency domain indices, such as high-frequency (HF) power, low-frequency (LF) power and LF/HF ratio, was observed. In this study, we focus on amplitude modulation of LF and HF oscillating component of HRV, and show that the non-Gaussianity of HRV as a mortality predictor correlates mainly with the amplitude variation of the LF oscillating component. In addition, it is also shown that increased heterogeneity of LF amplitude modulation is a significant mortality predictor in CHF patients (n=108).

Fourier power spectra of heart rate variability (HRV) exhibit 1/f-type scaling. Recently, to evaluate such scaling properties, detrended fluctuation analysis (DFA) has been widely used. In those studies, short-term (<11 beats) and long-term (>11 beats) scaling exponents have been commonly estimated, since those indices were defined in the original paper on DFA. However, the scaling range selection assuming the crossover point located on 11 beats is not based on systematic studies. Actually, spurious scaling exponents due to overfitting are sometimes observed. To address this problem, we here revisited the scaling properties in healthy subjects (n=122) and congestive heart failure patients (n=108). In particular, we address the following problem: (1) Which is the physiologically meaningful time unit, the subject's heartbeat or physical time? (2) Are the scaling ranges of HRV invariant? Although, in previous studies, the subject's heartbeat has been used as a standard time unit, we also studied re-sampled HRV time series. Our analysis revealed that most crossover points of the scaling behavior were located not on 11 beats, but on the very low frequency range (more than 25 seconds).

A pacemaker (PM) and an implantable cardioverter defibrillator (ICD) are devices that are inserted into the body to maintain regular heart rhythm in patients with serious heart rhythm problems. Among Japan's aging population, the number of patients requiring PM and ICD implantation has gradually and steadily increased. Therefore, a quantitative assessment of the future number of those patients is not only clinically, but also medical-economically and politically important. In this study, to develop a forecasting model for the number of patients requiring PM or ICD implantation, we analyzed past records of the number of PM and ICD implantation from 2006 to 2013 in Japan. Using a multiple regression analysis, we show the age and gender dependence of the number of PM and ICD implantation in each year, and propose a forecasting model based on age and gender composition rates of population. Moreover, as an application of our model, we estimate the future demand of PM and ICD devices in Japan.

Sleep disordered breathing (SDB) has been identified as mortality risk factor in patients with cardiovascular disease. Although the severity of SDB is quantified primarily by the apnea-hypopnea index (AHI), the average number of apneas and hypopneas per hour of sleep, it is not clear whether the AHI is a reliable index to evaluate an increased mortality risk associated with SDB in cardiovascular disease patients. To address this problem, we analyzed polysomnogram (PSG) data including nasal flow and pulse oximetry (SpO₂) level signals, and studied the association between characteristics of the PSG data and mortality in cardiovascular disease patients (n=112) with central sleep apnea due to Cheyne-Stokes breathing pattern. Compared to airflow-related parameters such as AHI, SpO₂ level-related parameters, such as cumulative time rate with desaturation episodes, was stronger predictors of all-cause mortality. This result suggests that characteristics of SpO₂ level drop related with SDB provide more important information to predict the mortality risk in cardiovascular disease patients than conventional AHI.