渡邉 英一

INTRODUCTION: Coronary artery and heart valve calcification is a risk factor for cardiovascular death in haemodialysis patients, so calcification prevention should be started as early as possible. Treatment with concomitant calcimimetics and low-dose vitamin D receptor activators (VDRAs) is available, but not enough evidence has been obtained on the efficacy of this regimen, particularly in patients with short dialysis duration. Therefore, this study will evaluate the efficacy and safety of early intervention with upacicalcet, a calcimimetic used to prevent coronary artery calcification in this patient population. METHODS AND ANALYSIS: This multicentre, open-label, randomised, parallel-group controlled study will compare an early intervention group, which received upacicalcet and a low-dose VDRA, with a conventional therapy group, which received a VDRA. The primary endpoint is a change in log coronary artery calcium volume score from baseline to 52 weeks. The main inclusion criteria are as follows: (1) age 18 years or older; (2) dialysis is planned or dialysis duration is less than 60 months; (3) intact parathyroid hormone (PTH) >240 pg/mL or whole PTH level>140 pg/mL; (4) serum-corrected calcium≥8.4 mg/dL and (5) Agatston score >30. The main exclusion criteria are as follows: (1) history of parathyroid intervention or fracture in the past 12 weeks; (2) history of myocardial infarction, stroke or leg amputation in the past 12 weeks; (3) history of coronary angioplasty and (4) heart failure of New York Heart Association class III or worse. ETHICS AND DISSEMINATION: The study will comply with the Declaration of Helsinki and the Japanese Clinical Trials Act. The study protocol has been approved by the Fujita Health University Certified Review Board (file no. CR22-052). Written informed consent will be obtained from all participants. Study results will be presented in academic meetings and peer-reviewed academic journals. TRIAL REGISTRATION NUMBER: jRCTs041220126.

Any reliable biomarker has to be specific, generalizable, and reproducible across individuals and contexts. The exact values of such a biomarker must represent similar health states in different individuals and at different times within the same individual to result in the minimum possible false-positive and false-negative rates. The application of standard cut-off points and risk scores across populations hinges upon the assumption of such generalizability. Such generalizability, in turn, hinges upon this condition that the phenomenon investigated by current statistical methods is ergodic, i.e., its statistical measures converge over individuals and time within the finite limit of observations. However, emerging evidence indicates that biological processes abound with nonergodicity, threatening this generalizability. Here, we present a solution for how to make generalizable inferences by deriving ergodic descriptions of nonergodic phenomena. For this aim, we proposed capturing the origin of ergodicity-breaking in many biological processes: cascade dynamics. To assess our hypotheses, we embraced the challenge of identifying reliable biomarkers for heart disease and stroke, which, despite being the leading cause of death worldwide and decades of research, lacks reliable biomarkers and risk stratification tools. We showed that raw R-R interval data and its common descriptors based on mean and variance are nonergodic and non-specific. On the other hand, the cascade-dynamical descriptors, the Hurst exponent encoding linear temporal correlations, and multifractal nonlinearity encoding nonlinear interactions across scales described the nonergodic heart rate variability more ergodically and were specific. This study inaugurates applying the critical concept of ergodicity in discovering and applying digital biomarkers of health and disease.

Background: We aimed to investigate the association between ventricular repolarization instability and sustained ventricular tachycardia and ventricular fibrillation (VT/VF) occurring within 48 h (acute-phase VT/VF) after the onset of acute coronary syndrome (ACS) and the prognostic role of repolarization instability and heart rate variability (HRV) after discharge from the hospital. Methods: We studied 572 ACS patients with a left ventricular ejection fraction >35%. The ventricular repolarization instability was assessed by the beat-to-beat T-wave amplitude variability (TAV) using high-resolution 24-h Holter ECGs recorded at a median of 11 days from the date of admission. We calculated the HRV parameters including the deceleration capacity (DC) and non-Gaussian index calculated on a 25 s timescale (λ25s). The DC and λ25s were dichotomized based on previous studies' thresholds. Results: Acute-phase VT/VF developed in 43 (7.5%) patients. In-hospital mortality was significantly higher among VT/VF patients (4.7% vs. 0.9%, p =.03). An adjusted logistic model showed that the maximum TAV (odds ratio 1.02, 95% confidence interval [CI] 1.00–1.29, p =.04) was associated with acute-phase VT/VF. During a median follow-up period of 2.1 years, 19 (3.3%) patients had cardiac deaths or resuscitated cardiac arrest. Acute-phase VT/VF (p =.12) and TAV (p =.72) were not significant predictors of survival. An age and sex-adjusted Cox model showed that the DC (p <.01), λ25s (p <.01), and emergency coronary intervention (p <.01) were independent predictors. Conclusion: T-wave amplitude variability was associated with acute-phase VT/VF, but the TAV was not predictive of survival post-discharge. The DC, λ25s, and emergency coronary intervention were independent predictors of survival.

When measuring physiological data, the central limit theorem typically implies a consistent variance, resulting in data that closely follow a Gaussian distribution. However, physiological measurements often deviate from this expectation, increasing variance due to nonlinear correlations across various scales. The challenge lies in testing these tails, which comprise only rare and extreme values. We introduce multiscale probability density function (PDF) analysis, a method that estimates this non-Gaussianity parameter for physiological fluctuations in each of multiple timescales. We gain valuable insights into the observed distributions with heavier tails and nonlinear correlations by exploring the relationship between non-Gaussianity and logarithmic scale. To maintain the fidelity of the original data, we incorporate an adaptive detrending filter into our multiscale PDF analysis. This filter effectively eliminates trends without distorting the distribution in a way that might risk artifactual signatures of non-Gaussianity. Additionally, we explain why multiscale PDF analysis is especially well suited for examining data that follow lognormal distributions. In the final stretch, we demonstrate how multiscale PDF analysis can provide fresh perspectives on heart rate variability and postural control. This innovative approach can facilitate diagnoses in health and disease while also deepening our comprehension of how constraints influence human physiological performance.

BACKGROUND: Circulating microRNAs (miRNAs, miR) have been considered as biomarkers reflecting the underlying pathophysiology in atrial fibrillation (AF). Nevertheless, miRNA expression in the peripheral blood samples might not reflect a cardiac phenomenon since most miRNAs are expressed in numerous organs. This study aimed to identify the cardiac-specific circulating miRNAs as biomarkers for AF. METHODS: Plasma samples were obtained from a luminal coronary sinus catheter (CS, cardiac-specific samples) and femoral venous sheath (FV, peripheral samples) in patients with AF and paroxysmal supraventricular tachycardia (control, CTL) undergoing catheter ablation. The circulating miRNA profiles were analyzed by small RNA sequencing. Differently expressed miRNAs between AF and CTL were identified in each sample of the CS and FV; miRNAs exhibiting similar expression patterns in the CS and FV samples were selected as candidates for cardiac-specific biomarkers. The selected miRNAs were related to the outcome of catheter ablation of AF. RESULTS: Small RNA sequencing detected 849 miRNAs. Among the top 30 most differently expressed miRNAs between AF and CTL, circulating hsa-miR-20b-5p, hsa-miR-330-3p, and hsa-miR-204-5p had a similar pattern in the CS and FV samples. Another set of peripheral blood samples was obtained from AF patients undergoing catheter ablation (n = 141). The expression of the miR-20b-5p and miR-330-3p, but not the miR-204-5p, negatively correlated with the echocardiographic left-atrial dimension and was decreased in patients with AF recurrence as compared to those without AF recurrence during a 1-year follow-up. CONCLUSION: Circulating miR-20b-5p and miR-330-3p can be cardiac-specific biomarkers for atrial remodeling progression and arrhythmia recurrence after catheter ablation in AF patients.

Contrast-associated acute kidney injury (CA-AKI) is a complication of percutaneous coronary intervention (PCI). Because proteinuria is a sentinel marker of renal dysfunction, we assessed its role in predicting CA-AKI in patients undergoing PCI. A total of 1,254 patients undergoing PCI were randomly assigned to a derivation (n = 840) and validation (n = 414) dataset. We identified the independent predictors of CA-AKI where CA-AKI was defined by the new criteria issued in 2020, by a multivariate logistic regression in the derivation dataset. We created a risk score from the remaining predictors. The discrimination and calibration of the risk score in the validation dataset were assessed by the area under the receiver-operating characteristic curves (AUC) and Hosmer–Lemeshow test, respectively. A total of 64 (5.1%) patients developed CA-AKI. The 3 variables of the risk score were emergency procedures, serum creatinine, and proteinuria, which were assigned 1 point each based on the correlation coefficient. The risk score demonstrated a good discriminative power (AUC 0.789, 95% CI 0.766–0.912) and significant calibration. It was strongly associated with the onset of CA-AKI (Cochran-Armitage test, p < 0.0001). Our risk score that included proteinuria was simple to obtain and calculate, and may be useful in assessing the CA-AKI risk before PCI.

Abstract Persistent atrial fibrillation (PeAF) may develop arrhythmogenic substrates of rotors/multiple wavelets. However, the ways in which pulmonary vein isolation (PVI) affects the dynamics of rotor/multiple wavelets in PeAF patients remain elusive. Real-time phase-mapping (ExTRa mapping, EXT) in the whole left atrium (LA) was performed during PeAF before and after PVI (n = 111). The percentage of time in which rotor/multiple wavelets (phase singularities) was observed during each 5-s phase-mapping recording (non-passive activation ratio, %NP) was measured as an index of its burden. The mapping areas showing %NP ≥ 50% were defined as rotor/multiple-wavelet substrates (RSs). Before PVI, RSs were globally distributed in the LA. After PVI, %NP decreased (&lt; 50%) in many RSs (PVI-modifiable RSs) but remained high (≥ 50%) in some RSs, especially localized in the anterior/septum/inferior regions (PVI-unmodifiable RSs, 2.3 ± 1.0 areas/patient). Before PVI, vagal response (VR) to high-frequency stimulation was observed in 23% of RSs, especially localized in the inferior region. VR disappearance after PVI was more frequently observed in PVI-modifiable RSs (79%) than in PVI-unmodifiable RSs (55%, p &lt; 0.05), suggesting that PVI affects autonomic nerve activities and rotor/multiple wavelet dynamics. PVI-unmodifiable RSs were adjunctively ablated in 104 patients. The 1-year AT/AF-free survival rate was 70% in those with PVI alone (n = 115), and 86% in patients with the adjunctive ablation (log-rank test = 7.65, p &lt; 0.01). PVI suppresses not only ectopic firing but also rotor/multiple wavelets partly via modification of autonomic nerve activities. The adjunctive ablation of PVI-unmodifiable RSs improved the outcome in PeAF patients and might be a novel ablation strategy beyond PVI.

Background: To determine the rate of undiagnosed atrial fibrillation (AF) we screened for AF using an oscillometric blood pressure (BP) monitor device followed by a single-lead handheld electrocardiogram (ECG), with confirmation by 12-lead ECG as the reference standard. Methods and Results: From October 2017 to August 2019, 1,148 patients were enrolled without known AF, who were aged ≥65 years with moderate-to-high stroke risk, at 71 centers in Japan. After exclusion of 7 patients with confirmed AF at the index visit, 1,141 patients were asked to use an oscillometric BP monitor twice daily for 2 weeks (max: 4 weeks) to detect an irregular pulse. The BP monitor detected an irregular pulse in 481 patients, of which 1 patient had confirmed AF. Thereafter, 480 patients were instructed to acquire ECGs twice daily for an additional 2 weeks (max: 4 weeks) using a single-lead handheld ECG device. The handheld ECG device detected irregular rhythm in 41 patients, of which 1 patient had confirmed AF. In total, undiagnosed AF was confirmed in 9 (0.8%) patients of the overall study cohort during the 24-week follow-up period. Conclusions: Sequential use of a BP monitor and handheld ECG for 4 weeks is a practical strategy for identifying undiagnosed AF in Japanese people at heightened risk of stroke.

Background: Telerehabilitation is an alternative clinic-based rehabilitation. A remote monitoring (RM) system attached to a cardiac rhythm device can collect physiological data and the device function. This study aimed to evaluate the safety and feasibility of telerehabilitation supervised by an RM in patients receiving cardiac resynchronization therapy (CRT). Methods: A single group pre–post exercise program was implemented for 3 months in 18 CRT recipients. The exercise regimen consisted of walking a prescribed number of steps based on a 6-min walk distance (6MWD) achieved at baseline. The patients were asked to exercise 3 to 5 times per week for up to 30 min per session, wearing an accelerometer to document the number of steps taken. The safety was assessed by the heart failure hospitalizations and all-cause death. The feasibility was measured by the improvement in the quality of life (QOL) using the EuroQol 5 dimensions, and daily active time measured by the CRT, 6MWD, B-type natriuretic peptide (BNP) level, and left ventricular ejection fraction (LVEF). Results: No patients had heart failure hospitalizations or died. No patients had any ventricular tachyarrhythmias. One patient needed to suspend the exercise due to signs of exacerbated heart failure by the RM. Compared to baseline, there were significant improvements in the QOL (−0.037, p <.05), active time (1.12%/day, p <.05), and 6MWD (11 m, p <.001), but not the BNP (–32.4 pg/ml, p =.07) or LVEF (0.28%, p =.55). Conclusions: Three months of RM-guided walking exercise in patients with CRT significantly increased the QOL, active time, and exercise capacity without any adverse effects.

The early detection of acute myocardial infarction, which is caused by lifestyle-related risk factors, is essential because it can lead to chronic heart failure or sudden death. Echocardiography, among the most common methods used to detect acute myocardial infarction, is a noninvasive modality for the early diagnosis and assessment of abnormal wall motion. However, depending on disease range and severity, abnormal wall motion may be difficult to distinguish from normal myocardium. As abnormal wall motion can lead to fatal complications, high accuracy is required in its detection over time on echocardiography. This study aimed to develop an automatic detection method for acute myocardial infarction using convolutional neural networks (CNNs) and long short-term memory (LSTM) in echocardiography. The short-axis view (papillary muscle level) of one cardiac cycle and left ventricular long-axis view were input into VGG16, a CNN model, for feature extraction. Thereafter, LSTM was used to classify the cases as normal myocardium or acute myocardial infarction. The overall classification accuracy reached 85.1% for the left ventricular long-axis view and 83.2% for the short-axis view (papillary muscle level). These results suggest the usefulness of the proposed method for the detection of myocardial infarction using echocardiography.

BACKGROUND: Noninvasive electrocardiographic markers (NIEMs) are promising arrhythmic risk stratification tools for assessing the risk of sudden cardiac death. However, little is known about their utility in patients with chronic kidney disease (CKD) and organic heart disease. This study aimed to determine whether NIEMs can predict cardiac events in patients with CKD and structural heart disease (CKD-SHD). METHODS: We prospectively analyzed 183 CKD-SHD patients (median age, 69 years [interquartile range, 61-77 years]) who underwent 24-h ambulatory electrocardiographic monitoring and assessed the worst values for ambulatory-based late potentials (w-LPs), heart rate turbulence, and nonsustained ventricular tachycardia (NSVT). The primary endpoint was the occurrence of documented lethal ventricular tachyarrhythmias (ventricular fibrillation or sustained ventricular tachycardia) or cardiac death. The secondary endpoint was admission for cardiovascular causes. RESULTS: Thirteen patients reached the primary endpoint during a follow-up period of 24 ± 11 months. Cox univariate regression analysis showed that existence of w-LPs (hazard ratio [HR] = 6.04, 95% confidence interval [CI]: 1.4-22.3, p = .007) and NSVT [HR = 8.72, 95% CI: 2.8-26.5: p < .001] was significantly associated with the primary endpoint. Kaplan-Meier analysis demonstrated that the combination of w-LPs and NSVT resulted in a lower event-free survival rate than did other NIEMs (p < .0001). No NIEM was useful in predicting the secondary endpoint, although the left ventricular mass index was correlated with the secondary endpoint. CONCLUSION: The combination of w-LPs and NSVT was a significant risk factor for lethal ventricular tachyarrhythmias and cardiac death in CKD-SHD patients.

BACKGROUND: Atrial fibrillation (AF) is a heterogeneous condition caused by various underlying disorders and comorbidities. A cluster analysis is a statistical technique that attempts to group populations by shared traits. Applied to AF, it could be useful in classifying the variables and complex presentations of AF into phenotypes of coherent, more tractable subpopulations. OBJECTIVES: This study aimed to characterize the clinical phenotypes of AF using a national AF patient registry using a cluster analysis. METHODS: We used data of an observational cohort that included 7406 patients with non-valvular AF enrolled from 158 sites participating in a nationwide AF registry (J-RHYTHM). The endpoints analyzed were all-cause mortality, thromboembolisms, and major bleeding. RESULTS: The optimal number of clusters was found to be 4 based on 40 characteristics. They were those with (1) a younger age and low rate of comorbidities (n = 1876), (2) a high rate of hypertension (n = 4579), (3) high bleeding risk (n = 302), and (4) prior coronary artery disease and other atherosclerotic comorbidities (n = 649). The patients in the younger/low comorbidity cluster demonstrated the lowest risk for all 3 endpoints. The atherosclerotic comorbidity cluster had significantly higher adjusted risks of total mortality (odds ratio [OR], 3.70; 95% confidence interval [CI], 2.37-5.80) and major bleeding (OR, 5.19; 95% CI, 2.58-10.9) than the younger/low comorbidity cluster. CONCLUSIONS: A cluster analysis identified 4 distinct groups of non-valvular AF patients with different clinical characteristics and outcomes. Awareness of these groupings may lead to a differentiated patient management for AF.

The outbreak of coronavirus disease 19 (COVID-19) has had a great impact on medical care. During the COVID-19 pandemic, the rate of hospital admissions has been lower and the rate of in-hospital mortality has been higher in patients with acute coronary syndrome (ACS) in Western countries. However, in Japan, it is unknown whether the COVID-19 pandemic has affected the incidence of ACS. In the study, eleven hospitals in the Tokai region participated. Among enrolled hospital, we compared the incidence of ACS during the COVID-19 pandemic (April and May, 2020) with that in equivalent months in the preceding year as the control. During the study period; April and May 2020, 248 patients with ACS were admitted. Compared to April and May 2019, a decline of 8.1% [95% confidence interval (CI) 5.2-12.1; P = 0.33] in admissions for ACS was observed between April and May 2020. There was no significant difference in the strategy for revascularization and in-hospital deaths between 2019 and 2020. In conclusion, the rate of admission for ACS slightly decreased during the COVID-19 pandemic, compared to the same months in the preceding year. Moreover, degeneration of therapeutic procedures for ACS did not occur.

The prognostic role of D-dimer in different types of heart failure (HF) is poorly understood. We investigated the prognostic value of D-dimer on admission, both independently and in combination with the Get With The Guidelines-Heart Failure (GWTG-HF) risk score and N-terminal pro-B-type natriuretic peptide (NT-proBNP), in patients with preserved left ventricular ejection fraction (LVEF) and acute decompensated HF (HFpEF) or reduced LVEF (HFrEF). Baseline D-dimer levels were measured on admission in 1670 patients (mean age: 75 years) who were hospitalized for worsening HF. Of those patients, 586 (35%) were categorized as HFpEF (LVEF ≥ 50%) and 1084 as HFrEF (LVEF < 50%). During the 12-month follow-up period after admission, 360 patients died. Elevated levels (at least the highest tertile value) of D-dimer, GWTG-HF risk score, and NT-proBNP were all independently associated with mortality in all HFpEF and HFrEF patients (all p < 0.05). Adding D-dimer to a baseline model with a GWTG-HF risk score and NT-proBNP improved the net reclassification and integrated discrimination improvement for mortality greater than the baseline model alone in all populations (all p < 0.001). The number of elevations in D-dimer, GWTG-HF risk score, and NT-proBNP were independently associated with a higher risk of mortality in all study populations (HFpEF and HFrEF patients; all p < 0.001). The combination of D-dimer, which is independently predictive of mortality, with the GWTG-HF risk score and NT-proBNP could improve early prediction of 12-month mortality in patients with acute decompensated HF, regardless of the HF phenotype.

It has been recognized that heart rate variability (HRV), defined as the fluctuation of ventricular response intervals in atrial fibrillation (AFib) patients, is not completely random, and its nonlinear characteristics, such as multiscale entropy (MSE), contain clinically significant information. We investigated the relationship between ischemic stroke risk and HRV with a large number of stroke-naïve AFib patients (628 patients), focusing on those who had never developed an ischemic/hemorrhagic stroke before the heart rate measurement. The CHA2DS2 − VASc score was calculated from the baseline clinical characteristics, while the HRV analysis was made from the recording of morning, afternoon, and evening. Subsequently, we performed Kaplan–Meier method and cumulative incidence function with mortality as a competing risk to estimate the survival time function. We found that patients with sample entropy (SE (S) ) ≥ 0.68 at 210 s had a significantly higher risk of an ischemic stroke occurrence in the morning recording. Meanwhile, the afternoon recording showed that those with SE (S)≥0.76 at 240 s and SE (S) ≥ 0.78 at 270 s had a significantly lower risk of ischemic stroke occurrence. Therefore, SE (S) at 210 s (morning) and 240 s ≤ s ≤ 270 s (afternoon) demonstrated a statistically significant predictive value for ischemic stroke in strokenaïve AFib patients.

BACKGROUND: Blunted cyclic variation of heart rate (CVHR), measured as a decrease in CVHR amplitude (Acv), predicts mortality risk after acute myocardial infarction (AMI). However, Acv also can be reduced in mild sleep apnea with mild O2 desaturation. We investigated whether Acv's predictive power for post-AMI mortality could be improved by considering the effect of sleep apnea severity. METHODS: In 24-hr ECG in 265,291 participants of the Allostatic State Mapping by Ambulatory ECG Repository project, sleep apnea severity was estimated by the frequency of CVHR (Fcv) measured by an automated algorithm for auto-correlated wave detection by adaptive threshold (ACAT). The distribution of Acv on the Acv-Fcv relation map was modeled by percentile regression, and a function converting Acv into percentile value was developed. In the retrospective cohort of the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study, consisting of 673 survivors and 44 non-survivors after AMI, the mortality predictive power of percentile Acv calculated by the function was compared with that of unadjusted Acv. RESULTS: Among the ALLSTAR ECG data, low Acv values appeared more likely when Fcv was low. The logistic regression analysis for mortality in the ENRICHD cohort showed c-statistics of 0.667 (SE, 0.041), 0.817 (0.035), and 0.843 (0.030) for Fcv, unadjusted Acv, and the percentile Acv, respectively. Compared with unadjusted Acv, the percentile Acv showed a significant net reclassification improvement of 0.90 (95% CI, 0.51-1.42). CONCLUSIONS: The predictive power of Acv for post-AMI mortality is improved by considering its relation to sleep apnea severity estimated by Fcv.

BACKGROUND: Functional capacity (FC) correlates with mortality in various cardiovascular diseases. The aim of this study was to examine whether cardiac pacemaker implantations improve the FC and affect the prognosis. METHODS AND RESULTS: We prospectively enrolled 621 de novo pacemaker recipients (age 76 ± 9 years, 50.7% male). The FC was assessed by metabolic equivalents (METs) during the implantation and periodically thereafter. The patients were a priori classified into poor FC (<2 METs, n = 40), moderate FC (2 ≤ METs < 4, n = 239), and good FC (≥4 METs, n = 342). Three months after the pacemaker implantation, poor FC or moderate FC patients improved to a good FC by 43%. The distribution of the three FCs remained at those levels until after 1 year of follow-up (P = .18). During a median follow-up of 2.4 years, 71 patients (11%) had cardiovascular hospitalizations and 35 (5.6%) all-cause death. A multivariate Cox analysis revealed that a poor FC at baseline was an independent predictor of both cardiovascular hospitalization (hazard ratio [HR] 2.494, P = .012) and all-cause death (HR 3.338, P = .016). One year after the pacemaker implantation, the eight who remained with a poor FC had a high mortality rate of 37.5% (P < .01). CONCLUSION: Approximately half of the poor or moderate FC patients improved to good FC 3 months after the pacemaker implantation. The baseline FC predicted the prognosis, and patients with an improved FC after the pacemaker implantation had a better prognosis.

AIM: We investigated the relationship between small dense low-density cholesterol (sdLDL-C) and risk of major adverse cardiovascular events (MACE) in patients treated with high- or low-dose statin therapy. METHODS: This was a prospective case-cohort study within the Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study, a randomized trial of high- or low-dose (4 or 1 mg/d pitavastatin, respectively) statin therapy, in patients with stable coronary artery disease (CAD). Serum sdLDL-C was determined using an automated homogenous assay at baseline (randomization after a rule-in period, ＞1 month with 1 mg/d pitavastatin) and 6 months after randomization, in 497 MACE cases, and 1543 participants randomly selected from the REAL-CAD study population. RESULTS: High-dose pitavastatin reduced sdLDL-C by 20% than low-dose pitavastatin (p for interaction ＜0.001). Among patients receiving low-dose pitavastatin, baseline sdLDL-C demonstrated higher MACE risk independent of LDL-C (hazard ratio [95% confidence interval], 4th versus 1st quartile, 1.67 [1.04-2.68]; p for trend=0.034). High-dose (versus low-dose) pitavastatin reduced MACE risk by 46% in patients in the highest baseline sdLDL-C quartile (＞34.3 mg/dL; 0.54 [0.36-0.81]; p=0.003), but increased relative risk by 40% in patients with 1st quartile (≤ 19.5 mg/dL; 1.40 [0.94-2.09]; p=0.099) and did not alter risk in those in 2nd and 3rd quartiles (p for interaction=0.002). CONCLUSIONS: These findings associate sdLDL-C and cardiovascular risk, independent of LDL-C, in statin-treated CAD patients. Notably, high-dose statin therapy reduces this risk in those with the highest baseline sdLDL-C.

Background: Machine learning (ML) has emerged as a promising tool for risk stratification. However, few studies have applied ML to risk assessment of patients with atrial fibrillation (AF). Hypothesis: We aimed to compare the performance of random forest (RF), logistic regression (LR), and conventional risk schemes in predicting the outcomes of AF. Methods: We analyzed data from 7406 nonvalvular AF patients (median age 71 years, female 29.2%) enrolled in a nationwide AF registry (J-RHYTHM Registry) and who were followed for 2 years. The endpoints were thromboembolisms, major bleeding, and all-cause mortality. Models were generated from potential predictors using an RF model, stepwise LR model, and the thromboembolism (CHADS2 and CHA2DS2-VASc) and major bleeding (HAS-BLED, ORBIT, and ATRIA) scores. Results: For thromboembolisms, the C-statistic of the RF model was significantly higher than that of the LR model (0.66 vs. 0.59, p =.03) or CHA2DS2-VASc score (0.61, p <.01). For major bleeding, the C-statistic of RF was comparable to the LR (0.69 vs. 0.66, p =.07) and outperformed the HAS-BLED (0.61, p <.01) and ATRIA (0.62, p <.01) but not the ORBIT (0.67, p =.07). The C-statistic of RF for all-cause mortality was comparable to the LR (0.78 vs. 0.79, p =.21). The calibration plot for the RF model was more aligned with the observed events for major bleeding and all-cause mortality. Conclusions: The RF model performed as well as or better than the LR model or existing clinical risk scores for predicting clinical outcomes of AF.

COVID-19 is a global catastrophe with markedly reduced health and economy of human civilization. Heart rhythm disorder has also been impacted by this disease. This statement is the universal criteria for EP procedures in the new era, which we will face during COVID-19 pandemic. We described the methods of triage based on the severity of disease, the regional state of pandemic and supply of medical resources. This guidance will be the universal criteria for EP procedures in the new era, which we will face during and after the COVID-19 pandemic.

INTRODUCTION: Silent cerebral events (SCEs) are related to the potential thromboembolic risk in atrial fibrillation (AF) ablation. Periprocedural uninterrupted oral anticoagulation (OAC) reportedly reduced the risk of SCEs, but the incidence still remains. METHODS AND RESULTS: AF patients undergoing catheter ablation were eligible. All patients took non-vitamin K antagonist oral anticoagulants (NOACs; n = 248) or vitamin K antagonist (VKA; n = 37) for periprocedural OAC (>4 weeks) without interruption during the procedure. Brain magnetic resonance imaging was performed within 2 days after the procedure to detect SCEs. Clinical characteristics and procedure-related parameters were compared between patients with and without SCEs. SCEs were detected in 66 patients (23.1%; SCE[+]) but were not detected in 219 patients (SCE[-]). Age was higher in SCE[+] than in SCE[-] (66 ± 10 vs. 62 ± 12 years; p < .05). Persistent AF prevalence, CHADS2 /CHA2 DS2 -VASc scores, serum NT-ProBNP levels, left atrial dimension (LAD), and spontaneous echo contrast prevalence in transesophageal echocardiography significantly increased in SCE[+] versus SCE[-]. SCE[+] had lower baseline activated clotting time (ACT) before heparin injection and longer time to reach optimal ACT (>300 s) than SCE[-] (146 ± 27 vs. 156 ± 29 s and 44 ± 30 vs. 35 ± 25 min; p < .05, respectively). In multivariate analysis, age, LAD, baseline ACT, and time to reach the optimal ACT were predictors for SCEs. The average values of the ACT parameters were significantly different among NOACs/VKA. CONCLUSION: Age, LAD, and intraprocedural ACT kinetics significantly affect SCEs during AF ablation. Different anticoagulants have different impacts on ACT during the procedure, which should be considered when estimating the risk of SCEs.

© 2020 IEEE. In heart failure, early detection of exacerbation is required to avoid unnecessary hospitalization. Although respiration instability detected by a respiration sensor attached to the bed at home has been proposed, detection by a more popular general sensor is desired. Using the fact that the frequency of respiratory sinus arrhythmia ({F}-{RSA}) reflects the frequency of breathing ({F}-{B}), we developed a method to estimate the instability of {F}-{B} by analyzing the instability of {F}-{RSA} only using R-R interval time series obtained from nighttime ECG. In 69 healthy control subjects, the fluctuation of {F}-{RSA} reduced to 6.8 \pm 3.9{\%} of local mean during sleep, while it remained 16.4\pm 7.7{\%} and 17.5 \pm 5.8{\%} in sinus rhythm patients with heart failure who survived for 38-mo follow-up period after recording (n = 52) and those died during the follow-up ({n}=29), respectively. {F}-{RSA} instability detected by ECG during sleep may be used as a feature to screen patients with heart failure.

Introduction: Recent studies have demonstrated the feasibility of uninterrupted direct oral anticoagulants (DOACs) with a temporary switch to dabigatran ("dabigatran bridge") for atrial fibrillation (AF) ablation. We compared the effectiveness and safety between uninterrupted DOACs with and without the "dabigatran bridge" in patients taking factor Xa inhibitors. Methods: AF patients on factor Xa inhibitors (rivaroxaban/apixaban/edoxaban) undergoing catheter ablation were eligible (n = 348). Brain MRI was performed within 2 days after the procedure to detect silent cerebral events (SCEs). Rivaroxaban/apixaban/edoxaban were uninterruptedly used in 153 patients (Group 1); these DOACs were switched to dabigatran on the day of AF ablation in 195 patients (Group 2). After propensity score matching, the unfractionated heparin (UFH) amount and the activated clotting time (ACT) kinetics during the procedure, the SCE incidence, and the follow-up complications (30 days, thromboembolism and major/minor bleeding) in the two groups were compared. Results: Group 2 had higher initial ACT value and shorter time to optimal ACT (>300 seconds) than Group 1 (184 ± 36 s vs 145 ± 22 s, and 34 ± 29 s vs 43 ± 34 s, P < .05, respectively). Group 2 tended to require less amount of UFH to achieve optimal ACT than Group 1, but the total amount of UFH for the procedure was comparable. Group 2 had lower SCE incidence than Group 1 (16.2% vs 26.4%, P < .05). The prevalence of follow-up complications was unchanged between the two groups. Conclusions: Switching to dabigatran on the day of AF ablation decreases preclinical thromboembolic events with similar bleeding risk to uninterrupted factor Xa inhibitors.

BACKGROUND: Inflammation and skeletal muscle wasting often coexist in elderly populations, but few studies have examined their relationship in elderly heart failure (HF) patients. This study examined the relationship between inflammation and increased skeletal muscle proteolysis, reduced skeletal mass and strength, and their prognostic implications in elderly HF patients (> 65 years) using a random forest approach. METHODS: We prospectively enrolled consecutive elderly HF patients (n = 78) and age- and sex-matched control subjects (n = 83). We measured the interleukin (IL)-6, C-reactive protein (CRP), and B-type natriuretic peptide (BNP) levels, lower limb muscle mass and strength, and 6-min walk distance. The amount of muscle proteolysis was determined by urinary 3-methylhystidine, normalized by creatinine (3-MH/Cr). The composite endpoint was defined as all-cause death or hospitalizations due to worsening HF. RESULTS: Compared to controls, elderly HF patients had a significantly higher IL-6, CRP, BNP, and 3-MH/Cr, and exhibited a reduced lower limb muscle mass and strength. A correlation analysis demonstrated significant positive correlations between the inflammatory cytokine levels and 3-MH/Cr and BNP, and negative correlations with the lower limb muscle mass and strength, and 6-min walk distance. During a median follow-up of 2.4-years, 24 patients reached the endpoint. A random forest model revealed that inflammatory cytokines, skeletal muscle wasting, and the BNP had greater effects on the risk prediction. The algorithm achieved an area under the receiver operating characteristic curve of 0.887 (95% CI, 0.772-1.000). CONCLUSION: This study provided evidence of the association between inflammation and increased skeletal muscle proteolysis, reduced skeletal mass and strength, and their prognostic roles in elderly HF patients.

BACKGROUND: Current expert consensus recommends remote monitoring for cardiac implantable electronic devices, with at least annual in-office follow-up. We studied safety and resource consumption of exclusive remote follow-up (RFU) in pacemaker patients for 2 years. METHODS: In Japan, consecutive pacemaker patients committed to remote monitoring were randomized to either RFU or conventional in-office follow-up (conventional follow-up) at twice yearly intervals. RFU patients were only seen if indicated by remote monitoring. All returned to hospital after 2 years. The primary end point was a composite of death, stroke, or cardiovascular events requiring surgery, and the primary hypothesis was noninferiority with 5% margin. RESULTS: Of 1274 randomized patients (50.4% female, age 77±10 years), 558 (RFU) and 550 (Conventional follow-up) patients reached either the primary end point or 24 months follow-up. The primary end point occurred in 10.9% and 11.8%, respectively (P=0.0012 for noninferiority). The median (interquartile range) number of in-office follow-ups was 0.50 (0.50-0.63) in RFU and 2.01 (1.93-2.05) in conventional follow-up per patient-year (P<0.001). Insurance claims for follow-ups and directly related diagnostic procedures were 18 800 Yen (16 500-20 700 Yen) in RFU and 21 400 Yen (16 700-25 900 Yen) in conventional follow-up (P<0.001). Only 1.4% of remote follow-ups triggered an unscheduled in-office follow-up, and only 1.5% of scheduled in-office follow-ups were considered actionable. CONCLUSIONS: Replacing periodic in-office follow-ups with remote follow-ups for 2 years in pacemaker patients committed to remote monitoring does not increase the occurrence of major cardiovascular events and reduces resource consumption. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01523704.

We prospectively investigated the prognostic value of urinary liver-type fatty-acid-binding protein (L-FABP) levels on hospital admission, both independently and in combination with serum creatinine-defined acute kidney injury (AKI), to predict long-term adverse outcomes in 1119 heterogeneous patients (mean age; 68 years) treated at medical (non-surgical) cardiac intensive care units (CICUs). Patients with stage 5 chronic kidney disease were excluded from the study. Of these patients, 47% had acute coronary syndrome and 38% had acute decompensated heart failure. The creatinine-defined AKI was diagnosed according to the "Kidney Disease: Improving Global Outcomes" criteria. The primary endpoint was a composite of all-cause death or progression to end-stage kidney disease, indicating the initiation of maintenance dialysis therapy or kidney transplantation. Creatinine-defined AKI occurred in 207 patients, with 44 patients having stage 2 or 3 disease. During a mean follow-up period of 41 months after enrollment, the primary endpoint occurred in 242 patients. Multivariate Cox regression analyses revealed L-FABP levels as independent predictors of the primary endpoint (p < 0.001). Adding L-FABP to a baseline model with established risk factors further enhanced reclassification and discrimination beyond that of the baseline model alone, for primary-endpoint prediction (both; p < 0.01). On Kaplan-Meier analyses, increased L-FABP (≥4th quintile value of 9.0 ng/mL) on admission or presence of creatinine-defined AKI, correlated with an increased risk of the primary endpoint (p < 0.001). Thus, urinary L-FABP levels on admission are potent and independent predictors of long-term adverse outcomes, and they might improve the long-term risk stratification of patients admitted at medical CICUs, when used in combination with creatinine-defined AKI.

BACKGROUND: Recent guidelines have stated that left ventricular ejection fraction (LVEF) is the gold standard marker for identifying patients at risk for cardiac mortality. However, little information is present regarding electrocardiographic (ECG) markers. This study aimed to assess ECG markers for predicting mortality or serious arrhythmia in patients with structural heart disease (SHD). METHODS: In total, 1829 patients were enrolled into the Japanese Multicenter Observational Prospective Study (JANIES study). In this study, we analyzed data of 719 patients (569 men, age 64 ± 13 years) with SHD including mainly ischemic heart disease (65.8%). As ECG markers based on 24-hour Holter recordings, nonsustained ventricular tachycardia (NSVT), ventricular late potentials, and heart rate turbulence (HRT) were assessed. The primary endpoint was all-cause mortality, and the secondary endpoint was fatal arrhythmic events. RESULTS: During a mean follow-up of 21 ± 11 months, all-cause mortality was eventually observed in 39 patients (5.4%). Among those patients, 32 patients (82%) suffered from cardiac causes such as heart failure and arrhythmia. Multivariate Cox regression analysis showed that after adjustment for age and LVEF, documented NSVT [hazard ratio = 2.46, 95% confidence interval (CI): 1.16-5.18, p = 0.02] and abnormal HRT (hazard ratio = 2.40, 95% CI: 1.16-4.93, p = 0.02) were significantly associated with the primary endpoint. These two ECG markers also had significant predictive values with the secondary endpoint. The combined assessment of two ECG markers improved predictive accuracy. CONCLUSION: This study demonstrated that combined assessment of documented NSVT and abnormal HRT based on 24-hour Holter ECG recordings are recommended for predicting future serious events in this population.

A 14-year-old boy collapsed suddenly after a basketball game and was transported to our hospital after recovering from ventricular fibrillation by an automated external defibrillator. He had experienced loss of consciousness twice and has been examined for suspected long-QT syndrome at another hospital. The 12-lead electrocardiogram on admission revealed a prolonged QTc interval of 480 milliseconds. After the patient recovered without any sequelae, computed tomography revealed an anomalous left coronary artery arising from the opposite sinus of Valsalva and coursing between the aorta and the pulmonary artery. Furthermore, genetic testing identified a KCNE1-D85N abnormality. An anomalous coronary artery is one of the major causes of sudden death in young people; therefore, surgical revascularization is recommended for left coronary arteries arising from the contralateral sinus and coursing between the aorta and the pulmonary artery, regardless of myocardial ischemia. Transient myocardial ischemia may have exaggerated the instability from the arrhythmic substrate, even though KCNE1-D85N abnormalities alone are not thought to cause fatal arrhythmias. Besides routine electrocardiography, further examinations, including imaging and genetic testing, can characterize the pathophysiology of fatal cardiac disease.

Anticoagulants are prescribed for prevention of thromboembolic events (TE) of atrial fibrillation (AF), however, their effects have a negative impact on disastrous bleeding outcomes. Idarucizumab was developed to reverse the anticoagulation effects of dabigatran. This study aimed to retrospectively investigate the clinical efficacy and safety of idarucizumab in the setting of progressive emergent bleeding events associated with catheter ablation (CA). Dabigatran is given uninterruptedly as an anticoagulant in patients undergoing CA of AF. The capacity of idarucizumab to reverse the anticoagulant effects of dabigatran in patients with cardiac tamponade associated with CA was examined by measuring the activated partial thromboplastin time (aPTT), active clotting time (ACT), and prothrombin international normalizing ratio (PT-INR). The primary endpoint was effective hemostasis. This analysis included 21 patients receiving idarucizumab, given for restoration of hemostasis. In all 21 patients, hemostasis was restored at a median of 205.6 ± 14.8 min. Normal intraoperative cessation of bleeding was reported in 16 patients, and completion of hemostasis was also ascertained in the remaining four within 5 h. No TEs occurred within 72 h after the idarucizumab administration. Despite a significant reduction in the aPTT and ACT, no significant change was observed in PT-INR after administering idarucizumab. In emergency situations, idarucizumab was able to reverse dabigatran within a relatively short period without any serious adverse events.

Implantable cardioverter-defibrillators (ICDs) improve survival in patients who are at risk of sudden death. However, inappropriate therapy is commonly given to ICD recipients, and this situation may be associated with an increased risk of death. This study aimed to construct a risk stratification scheme by using decision tree analysis in patients who received inappropriate ICD therapy.Mortality was calculated from a retrospective data analysis of a multicenter cohort involving 417 ICD recipients. Inappropriate therapy was defined as therapy for nonventricular arrhythmias, including sinus tachycardia, supraventricular tachycardia, atrial fibrillation/flutter, oversensing, and lead failure. Inappropriate therapy included antitachycardia pacing, cardioversion, and defibrillation. The prognostic factors were identified by a Cox proportional hazards regression analysis, and we constructed a decision tree.During an average follow-up of 5.2 years, 48 patients (12%) had all-cause death. A multivariate Cox hazard model revealed that the age (hazard ratio [HR] 1.06, P < 0.001), ln B-type natriuretic peptide (BNP) (HR 1.47, P = 0.02), nonsinus rhythm at implantation (HR 2.70, P < 0.05), and inappropriate therapy occurring during sedentary/awake conditions (HR 3.51, P = 0.001) correlated with an increased risk of mortality. An inappropriate therapy due to abnormal sensing (HR 0.16, P = 0.04) decreased the risk of mortality. Furthermore, a decision tree analysis stratified the patients well by using 4 covariates: BNP, activity at the time of inappropriate therapy, mechanism of inappropriate therapy, and baseline rhythm at ICD implantation (log-rank test, P < 0.0001).We identified the predictors of mortality in inappropriate ICD therapy recipients and constructed a risk stratification scheme by using decision tree analysis.

Background: Since warfarin is primarily bound to serum albumin, hypoalbuminemia is likely to increase the free fraction of warfarin and to increase the risk of bleeding. We prospectively evaluated the impact of serum albumin levels (ALB) on international normalized ratio of prothrombin time (PT-INR) control and hemorrhagic events in atrial fibrillation (AF) patients treated with warfarin. Methods: Seven hundred fifty-five non-valvular AF patients on warfarin were enrolled. PT-INR control and major bleeding events (MB, International Society on Thrombosis and Haemostasis) were prospectively followed and were related to ALB at enrollment. Results: Twenty-seven patients developed MB during 1-year follow-up. In univariate/multivariate analyses, ALB (OR = 0.49, 95% CI 0.26-0.99, p = 0.04) and hemoglobin levels (OR = 0.78, 95% CI 0.65-0.92, p = < 0.01) were predictive for the annual risk of MB. In Spearman's rank correlation analysis, the baseline ALB was inversely correlated with the percentage of the time in PT-INR > 3.0 (ρ = -0.15, p < 0.0001), but neither 2.0 ≤ PT-INR ≤ 3.0 (ρ = 0.056, p = 0.13) nor PT-INR < 2.0 (ρ = -0.008, p = 0.82) during 1-year follow-up, suggesting that patients with low ALB had a directional tendency to be supratherapeutic control of PT-INR. The ROC curve showed that a cutoff of ALB was 3.6 g/dl to identify MB (AUC = 0.65). In Kaplan-Meier analysis, patients with ALB <3.6 g/dl (23/80, 29%) had more MB than those with ALB ≥3.6 g/dl (87/675, 13%, log-rank = 16.80, p < 0.0001) during long-term follow-up (3.8 ± 2.0 years). Conclusions: Hypoalbuminemia increases the likelihood of supratherapeutic PT-INR control and the risk of MB. ALB can be a practical surrogate marker to prevent excessive warfarin control and warfarin-related MB.

OBJECTIVE: Numerous indices were devised for the statistical characterization of temporal dynamics of heart rate variability (HRV) with the aim to discriminate between healthy subjects and nonhealthy patients. Elaborating on the concepts of (multi)fractal and nonlinear analyses, the present contribution defines and studies formally novel non Gaussian multiscale representations. METHODS: A methodological framework for non Gaussian multiscale representations constructed on wavelet p-leaders is developed, relying a priori neither on exact scale-free dynamics nor on predefined forms of departure from Gaussianity. Its versatility in quantifying the strength and nature of departure from Gaussian is analyzed theoretically and numerically. The ability of the representations to discriminate between healthy subjects and congestive heart failure (CHF) patients, and between survivors and nonsurvivor CHF patients, is assessed on a large cohort of 198 subjects. RESULTS: The analysis leads to conclude that i) scale-free and multifractal dynamics are observed, both for healthy subjects and CHF patients, for time scales shorter than [Formula: see text]; ii) a circadian evolution of multifractal and non Gaussian properties of HRV is evidenced for healthy subjects, but not for CHF patients; iii) non Gaussian multiscale indices possess high discriminative abilities between survivor and nonsurvivor CHF patients, at specific time scales ([Formula: see text] and [Formula: see text]). CONCLUSIONS: The non Gaussian multiscale representations provide evidence for the existence of short-term cascade-type multifractal mechanisms underlying HRV for both healthy and CHF subjects. A circadian evolution of this mechanism is only evidenced for the healthy group, suggesting an alteration of the sympathetic-parasympathetic balance for CHF patients. SIGNIFICANCE: Results obtained for a large cohort of subjects suggest that the novel non Gaussian indices might robustly quantify crucial information for clinical risk stratification in CHF patients.

BACKGROUND: Cardiac wall motion abnormality (WMA) is a common complication in patients with subarachnoid hemorrhage (SAH) and is one determinant of their prognosis. The aim of this study was to examine whether the electrocardiography (ECG) findings at admission could predict WMA commonly observed after SAH. MATERIALS AND METHODS: We studied 161 SAH patients with SAH who were hospitalized in our institution between April 2007 and November 2010. We performed bedside 2-dimensional transthoracic echocardiography and 12-lead surface ECG within 24hours of SAH onset. Each of the following ECG changes was scored as having 1 point: ST elevation, ST depression and T wave inversion. We summed up the points in every patient and compared with WMA evaluated by echocardiography. RESULTS: The study subjects were classified into 2 groups based on the presence of WMA. Multivariate analysis revealed that ST elevation, ST depression and T wave inversion were strong independent predictors of WMA. Receiver operating characteristic curve determined that the threshold value to predict WMA was 4 points (sensitivity 86.5%, specificity 83.1%, AUC 0.94, P < .0001). CONCLUSIONS: In conclusion, a novel ECG score may well predict WMA after SAH which may associate with an increased risk of mortality.

BACKGROUND: In atrial fibrillation (AF) patients, the effect of direct oral anticoagulant (DOACs) therapy on the incidence of left atrial appendage thrombus (LAT) remains poorly investigated. This study examined the prevalence and risk factors of LAT in AF patients on DOACs undergoing catheter ablation, and sought an anticoagulation strategy for LAT. Methods and Results: In 407 AF patients on DOACs, transesophageal echocardiography (TEE) was performed 1 day before ablation. If patients had LAT, initial DOACs were switched to dabigatran (300 mg) or warfarin based on their renal function; TEE was repeated after treatment for ≥4 weeks. LAT was detected in 18 patients (4.4%). The prevalence of persistent AF and low-dose treatment/inappropriate dose reduction of DOACs, CHADS2/CHA2DS2-VASc scores, serum N-terminal pro-brain natriuretic peptide levels, and LA dimension/LA volume index significantly increased in patients with LAT vs. those without LAT. AF rhythm on TEE and spontaneous echo contrast also increased in patients with LAT; LA appendage flow velocity decreased. In the multivariate analysis, persistent AF and inappropriately reduced DOAC dose were risk factors for LAT. On repeat TEE, LAT had disappeared in 13 of 16 patients treated with dabigatran and in 2 of 2 patients treated with warfarin. CONCLUSIONS: DOACs still carry a finite risk of LAT in AF patients. Inappropriately reduced DOAC dose should be avoided to minimize the thromboembolic risk. Regular-dose dabigatran may have therapeutic efficacy against LAT.

Multifractal analysis of human heartbeat dynamics has been demonstrated to provide promising markers of Congestive Heart Failure (CHF). Yet, it crucially builds on the interpolation of RR intervals series, which has been generically performed with limited links to CHF pathophysiology. We devise a novel methodology estimating multifractal autonomic dynamics from heartbeat-derived series defined in the continuous time. We hypothesize that markers estimated from our novel framework are also effective for mortality prediction in severe CHF. We merge multifractal analysis within a methodological framework based on inhomogeneous point process models of heartbeat dynamics. Specifically, wavelet coefficients and wavelet leaders are computed over measures extracted from instantaneous statistics of probability density functions characterizing and predicting the time until the next heartbeat event occurs. The proposed approach is tested on data from 94 CHF patients, aiming at predicting survivor and non-survivor individuals as determined after a 4 years follow up. Instantaneous markers of vagal and sympatho-vagal dynamics display power-law scaling for a large range of scales, from s to s. Using standard SVM algorithms, the proposed inhomogeneous point-process representation based multifractal analysis achieved the best CHF mortality prediction accuracy of 79.11 % (sensitivity 90.48%, specificity 67.74%). Our results suggest that heartbeat scaling and multifractal properties in CHF patients are not generated at the sinus-node level, but rather by the intrinsic action of vagal short-term control and of sympatho-vagal fluctuations associated with circadian cardiovascular control, especially within the VLF band. These markers might provide critical information in devising a clinical tool for individualized prediction of survivor and non-survivor CHF patients.

BACKGROUND: The early prediction of acute kidney injury (AKI) can facilitate timely intervention and prevent complications. We aimed to understand the predictive value of urinary liver-type fatty-acid binding protein (L-FABP) levels on admission to medical (non-surgical) cardiac intensive care units (CICUs) for AKI, both independently and in combination with serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. METHODS: We prospectively investigated the predictive value of L-FABP and NT-proBNP for AKI in a large, heterogeneous cohort of patients treated in medical CICUs. Baseline urinary L-FABP and serum NT-proBNP were measured on admission. AKI was diagnosed according to the Kidney Disease: Improving Global Outcomes criteria. We studied 1273 patients (mean age, 68 years), among whom 46% had acute coronary syndromes, 38% had acute decompensated heart failure, 5% had arrhythmia, 3% had pulmonary hypertension, 2% had acute aortic syndrome, 2% had infective endocarditis, and 1% had Takotsubo cardiomyopathy. RESULTS: Urinary L-FABP levels correlated with serum NT-proBNP levels (r = 0.17, p < 0.0001). AKI occurred in 224 patients (17.6%), including 48 patients with stage 2 or 3 disease. Patients who developed AKI had higher one-week and 6-month mortality than those who did not develop AKI (p = 0.0002 and p = 0.003, respectively). In the multivariate logistic analysis, both L-FABP (p < 0.0001) and NT-proBNP (p = 0.006) were independently associated with the development of AKI. Adding L-FABP and NT-proBNP to a baseline model that included established risk factors further improved reclassification (p < 0.001) and discrimination (p < 0.01) beyond that of the baseline model or any single biomarker individually. CONCLUSIONS: Urinary L-FABP and serum NT-proBNP levels on admission are independent predictors of AKI, and when used in combination, improve early prediction of AKI in patients hospitalized at medical CICUs.

Differences in successive R-R intervals (RRIs) were normalized by RRIs before and after the indexing beats (normalized DRs) in individuals with normal sinus rhythm (NSR) and 98.89% of normalized DRs were found to distribute within mean ± 0.100 (≒mean ± 3SD), whereas 73.47% were out of this range in atrial fibrillation (AF). When 7 out 20 normalized DRs fell outside of 0.000 ± 0.100, NSR (n = 129) and AF (n = 108) could be discriminated with high sensitivity, specificity, and predictive values (&gt 99.0% for all). This method will be used in detecting AF candidates from a small number of heart beats or arterial pulses.

BACKGROUND: Atrial fibrillation (AF) is an identified risk factor for ischemic strokes (IS). AF causes a loss in atrial contractile function that favors the formation of thrombi, and thus increases the risk of stroke. Also, AF produces highly irregular and complex temporal dynamics in ventricular response RR intervals. Thus, it is hypothesized that the analysis of RR dynamics could provide predictors for IS. However, these complex and nonlinear dynamics call for the use of advanced multiscale nonlinear signal processing tools. OBJECTIVES: The global aim is to investigate the performance of a recently-proposed multiscale and nonlinear signal processing tool, the scattering transform, in predicting IS for patients suffering from AF. METHODS: The heart rate of a cohort of 173 patients from Fujita Health University Hospital in Japan was analyzed with the scattering transform. First, p-values of Wilcoxon rank sum tests were used to identify scattering coefficients achieving significant (univariate) discrimination between patients with and without IS. Second, a multivariate procedure for feature selection and classification, the Sparse Support Vector Machine (S-SVM), was applied to predict IS. RESULTS: Groups of scattering coefficients, located at several time-scales, were identified as significantly higher (p-value < 0.05) in patients who developed IS than in those who did not. Though the overall predictive power of these indices remained moderate (around 60 %), it was found to be much higher when analysis was restricted to patients not taking antithrombotic treatment (around 80 %). Further, S-SVM showed that multivariate classification improves IS prediction, and also indicated that coefficients involved in classification differ for patients with and without antithrombotic treatment. CONCLUSIONS: Scattering coefficients were found to play a significant role in predicting IS, notably for patients not receiving antithrombotic treatment. S-SVM improves IS detection performance and also provides insight on which features are important. Notably, it shows that AF patients not taking antithrombotic treatment are characterized by a slow modulation of RR dynamics in the ULF range and a faster modulation in the HF range. These modulations are significantly decreased in patients with IS, and hence have a good discriminant ability.

Heart failure (HF) is classified into three clinical subtypes: HF with a preserved ejection fraction (HFpEF: EF ≥ 50%), HF with a mid-range ejection fraction (HFmrEF: 40 ≤ EF < 49%), and HF with a reduced ejection fraction (HFrEF: EF < 40%). These types often coexist with atrial fibrillation (AF). We investigated the rate of strokes/systemic embolisms (SSEs) in AF patients with HFpEF (AF-HFpEF) compared to that in those with HFrEF (AF-HFrEF: HFmrEF and HFrEF), and examined the independent predictors. We prospectively enrolled 1350 patients admitted to our hospital for worsening HF. We identified 301 patients with either AF-HFpEF (n = 129, 43%) or AF-HFrEF (n = 172, 57%). Compared to the patients with AF-HFrEF, those with AF-HFpEF were older and more likely to be female. Oral anticoagulant use was 63 vs. 66%, respectively. During a mean follow-up period of 26 months, 21 (7%) and 66 (22%) patients had SSEs and all-cause death, respectively. The crude annual rates of SSEs (3.9 vs. 2.7%, P = 0.47) were similar between the groups. In a multivariate Cox regression analysis, an age ≥ 75 years (hazard ratio 2.14, 95% confidence interval 1.32-3.58, P < 0.01) and the plasma B-type natriuretic peptide (BNP) level ≥ 341 pg/ml (hazard ratio 1.60, 95% confidence interval 1.07-2.39, P < 0.05) were associated with SSEs. The EF was not an independent predictor of SSEs (hazard ratio 1.01, 95% confidence interval 0.98-1.04, P = 0.51). There were no significant differences in the rates of SSEs between AF-HFpEF and AF-HFrEF. Patients with HF and concomitant AF should be treated with anticoagulants irrespective of EF.