Impact of High-Voltage Device Implantation in Elderly Japanese Patients With Heart Failure as Primary Prevention　- Post Hoc Analysis of HINODE.

BACKGROUND: Despite an increased incidence of chronic heart failure (HF) and sudden cardiac death (SCD), the use of implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT) is much lower in Japan than in Western countries. The HF Indication and SCD Prevention Trial Japan (HINODE) prospectively assessed the mortality rate, appropriately treated ventricular arrhythmias (VA), and HF in Japanese patients with a higher risk of HF.Methods and Results: HINODE consisted of ICD, CRT-defibrillator (CRT-D), pacing, and non-device treatment cohorts. This subanalysis evaluated the impact of the implantation of high-voltage devices (HVD; ICD and CRT-D) in 171 Japanese patients. We compared all-cause mortality, VA, and HF events between elderly (age >70 years at study enrollment) and non-elderly HVD recipients. The estimated survival rate through 24 months in the HVD cohort was 85.8% (97.5% lower control limit 77.6%). The risk of all-cause mortality was increased for the elderly vs. non-elderly (hazard ratio [HR] 2.82; 95% confidence interval [CI] 1.01-7.91; P=0.039), but did not differ after excluding ICD patients with CRT-D indication (HR 2.32; 95% CI 0.79-6.78; P=0.11). There were no differences in VA and HF event-free rates between elderly and non-elderly HVD recipients (P=0.73 and P=0.55, respectively). CONCLUSIONS: Although elderly patients may have a higher risk of mortality in general, the benefit of HVD therapy in this group is comparable to that in non-elderly patients.

Impact of Preprocedural Frailty Status in Elderly Transvenous Pacemaker Recipients.

The number of TV-PM implantations in elderly people is increasing. Although frailty syndrome is common in elderly patients, the relationship between the pre-procedural frailty status and clinical outcomes has not been fully elucidated in elderly TV-PM recipients.This study included 103 consecutive patients over 80 years old who were newly implanted with a TV-PM (age 85.7 ± 4.2, 41.7% male). We assessed the relationship between the clinical outcome and predictive factors, especially for the pre-procedural frailty status after the TV-PM implantation. The pre-procedural frailty status was retrospectively assessed from the medical records and classified on the basis of impairments in 3 domains (walking, cognition, and activities of daily living). The primary endpoint was defined as a heart failure admission.During the follow-up period (4.1 ± 2.3 years), 20 patients (19.4%) met the primary endpoint. Frailty syndrome was identified in 40 patients (38.8%). In univariate analysis, the LVEF (HR 0.97, 95% CI 0.96-1.00 P = 0.0492), an RV pacing burden over 40% (HR 1.58, 95% CI 1.00-2.54 P = 0.0473), and presence of a frailty status (HR 1.82, 95% CI 1.13-2.87 P = 0.0134) were found to be statistically significant predictors for the study endpoint. In multivariate analysis, having frailty syndrome was the only predictive factor for a heart failure admission (HR 1.83, 95% CI 1.12-2.93 P = 0.0157).The presence of frailty syndrome and incidence of clinical events were high and a pre-procedural frailty status assessment was key in determining the clinical outcomes in TV-PM recipients over 80 years old.

Risk of Mortality Prediction Involving Time-Varying Covariates for Patients with Heart Failure Using Deep Learning.

Heart failure (HF) is challenging public medical and healthcare systems. This study aimed to develop and validate a novel deep learning-based prognostic model to predict the risk of all-cause mortality for patients with HF. We also compared the performance of the proposed model with those of classical deep learning- and traditional statistical-based models. The present study enrolled 730 patients with HF hospitalized at Toho University Ohashi Medical Center between April 2016 and March 2020. A recurrent neural network-based model (RNNSurv) involving time-varying covariates was developed and validated. The proposed RNNSurv showed better prediction performance than those of a deep feed-forward neural network-based model (referred as "DeepSurv") and a multivariate Cox proportional hazard model in view of discrimination (C-index: 0.839 vs. 0.755 vs. 0.762, respectively), calibration (better fit with a 45-degree line), and ability of risk stratification, especially identifying patients with high risk of mortality. The proposed RNNSurv demonstrated an improved prediction performance in consideration of temporal information from time-varying covariates that could assist clinical decision-making. Additionally, this study found that significant risk and protective factors of mortality were specific to risk levels, highlighting the demand for an individual-specific clinical strategy instead of a uniform one for all patients.

Exploring and Identifying Prognostic Phenotypes of Patients with Heart Failure Guided by Explainable Machine Learning.

Identifying patient prognostic phenotypes facilitates precision medicine. This study aimed to explore phenotypes of patients with heart failure (HF) corresponding to prognostic condition (risk of mortality) and identify the phenotype of new patients by machine learning (ML). A unsupervised ML was applied to explore phenotypes of patients in a derivation dataset (n = 562) based on their medical records. Thereafter, supervised ML models were trained on the derivation dataset to classify these identified phenotypes. Then, the trained classifiers were further validated on an independent validation dataset (n = 168). Finally, Shapley additive explanations were used to interpret decision making of phenotype classification. Three patient phenotypes corresponding to stratified mortality risk (high, low, and intermediate) were identified. Kaplan−Meier survival curves among the three phenotypes had significant difference (pairwise comparison p < 0.05). Hazard ratio of all-cause mortality between patients in phenotype 1 (n = 91; high risk) and phenotype 3 (n = 329; intermediate risk) was 2.08 (95%CI 1.29−3.37, p = 0.003), and 0.26 (95%CI 0.11−0.61, p = 0.002) between phenotype 2 (n = 142; low risk) and phenotype 3. For phenotypes classification by random forest, AUCs of phenotypes 1, 2, and 3 were 0.736 ± 0.038, 0.815 ± 0.035, and 0.721 ± 0.03, respectively, slightly better than the decision tree. Then, the classifier effectively identified the phenotypes for new patients in the validation dataset with significant difference on survival curves and hazard ratios. Finally, age and creatinine clearance rate were identified as the top two most important predictors. ML could effectively identify patient prognostic phenotypes, facilitating reasonable management and treatment considering prognostic condition.

Deep Learning-Based Recurrence Prediction of Atrial Fibrillation After Catheter Ablation.

BACKGROUND: Radiofrequency catheter ablation (RFCA) is an effective therapy for atrial fibrillation (AF). However, it the problem of AF recurrence remains. This study investigates whether a deep convolutional neural network (CNN) can accurately predict AF recurrence in patients with AF who underwent RFCA, and compares CNN with conventional statistical analysis.Methods and Results:Three-hundred and ten patients with AF after RFCA treatment, including 94 patients with AF recurrence, were enrolled. Nine variables are identified as candidate predictors by univariate Cox proportional hazards regression (CPH). A CNNSurv model for AF recurrence prediction was proposed. The model's discrimination ability is validated by a 10-fold cross validation method and measured by C-index. After back elimination, 4 predictors are used for model development, they are N-terminal pro-BNP (NT-proBNP), paroxysmal AF (PAF), left atrial appendage volume (LAAV) and left atrial volume (LAV). The average testing C-index is 0.76 (0.72-0.79). The corresponding calibration plot appears to fit well to a diagonal, and the P value of the Hosmer-Lemeshow test also indicates the proposed model has good calibration ability. The proposed model has superior performance compared with the DeepSurv and multivariate CPH. The result of risk stratification indicates that patients with non-PAF, higher NT-proBNP, larger LAAV and LAV would have higher risks of AF recurrence. CONCLUSIONS: The proposed CNNSurv model has better performance than conventional statistical analysis, which may provide valuable guidance for clinical practice.

Electrocardiogram Quality Assessment with a Generalized Deep Learning Model Assisted by Conditional Generative Adversarial Networks.

The electrocardiogram (ECG) is widely used for cardiovascular disease diagnosis and daily health monitoring. Before ECG analysis, ECG quality screening is an essential but time-consuming and experience-dependent work for technicians. An automatic ECG quality assessment method can reduce unnecessary time loss to help cardiologists perform diagnosis. This study aims to develop an automatic quality assessment system to search qualified ECGs for interpretation. The proposed system consists of data augmentation and quality assessment parts. For data augmentation, we train a conditional generative adversarial networks model to get an ECG segment generator, and thus to increase the number of training data. Then, we pre-train a deep quality assessment model based on a training dataset composed of real and generated ECG. Finally, we fine-tune the proposed model using real ECG and validate it on two different datasets composed of real ECG. The proposed system has a generalized performance on the two validation datasets. The model's accuracy is 97.1% and 96.4%, respectively for the two datasets. The proposed method outperforms a shallow neural network model, and also a deep neural network models without being pre-trained by generated ECG. The proposed system demonstrates improved performance in the ECG quality assessment, and it has the potential to be an initial ECG quality screening tool in clinical practice.

Safety and feasibility of implanting a transvenous implantable cardioverter defibrillator (TV-ICD) in the left axilla.

BACKGROUND: Transvenous implantable cardioverter defibrillator (TV-ICD) systems are commonly implanted in the left anterior chest because of an easier implantation and better defibrillation threshold. This study aimed to evaluate the safety and feasibility of left axillary implantations of TV-ICD systems. METHODS: We performed left axillary TV-ICD implantations and compared that to the major complication rate and operation time of the conventional TV-ICD implantation site (left anterior chest). The electrical parameter trends were also assessed in the left axilla group. RESULTS: Seventy-six consecutive patients were evaluated for the analysis. Thirty-one patients had their system implanted in the left axilla and the reasons for the implantations included 29 patients for cosmetic reasons and two for post-infection conditions. The operation time and major complication rate were similar between the two groups (left anterior chest vs. left axilla: 134±62.4 min vs. 114±33.5 min, p = .11, 1/45 patient, 2.2% [pocket hematoma] vs. 1/31 patient, 3.2% [lead dislodgement], p = .77). During the follow up period (4.9±2.3years), no lead interruptions were observed in either group. The electrical lead parameters at the time of the implantation and follow up were similar in the study group (R wave sensing 20.8±33.4 vs. 11.2±7.42 mv, p = .34; lead impedance 464±64.7 vs. 418±135ohm, p = .22; pacing threshold [at 0.4 ms] 1.0±0.76 vs. 1.21±0.93V, p = .49). CONCLUSION: TV-ICD implantations in the left axilla were performed safely without increasing the operation time as compared to the conventional ICD implantation site. ICD implantations in the left axilla are an alternative in those not suitable for implanting TV-ICDs in the conventional implantation site.

Impact of right atrial structural remodeling on recurrence after ablation for atrial fibrillation.

BACKGROUND: Recurrence of atrial fibrillation (AF) after pulmonary vein isolation (PVI) is associated with left atrial (LA) remodeling; however, its association with right atrial (RA) remodeling remains unclear. OBJECTIVE: This study aimed to identify whether RA structural remodeling could predict recurrence of AF after PVI. METHODS: This study prospectively analyzed 245 patients with AF who had undergone PVI. RA and LA volumes were determined by contrast-enhanced computed tomography. Atrial structural remodeling was defined as an atrial volume of ≥110 mL according to previous reports and receiver operating characteristic curve analysis. RESULTS: After excluding 32 patients, 213 patients were analyzed. During a follow-up period of 12 months, 41 patients (19%) demonstrated atrial arrhythmia recurrence after PVI. With the Cox proportional-hazards model, RA structural remodeling was the only predictor of arrhythmia recurrence (hazard ratio, 1.012; 95% confidence interval 1.003-1.021; P = .009). Kaplan-Meier analysis showed that arrhythmia recurrence was more frequent in the RA structural remodeling group compared with the group without RA remodeling (log-rank, P < .001), and the arrhythmia-free survival rates in these groups at 12 months were 68.0% and 91.4%, respectively. Additionally, there was a significant difference in recurrence-free survival after RA structural remodeling in each type of AF (log-rank, P < .001). CONCLUSIONS: RA structural remodeling is a useful predictor of clinical outcome after PVI regardless of the type of AF. Our results suggest that patients without RA structural remodeling may be good candidates for successful ablation with PVI.

Impact of atrial mitral and tricuspid regurgitation on atrial fibrillation recurrence after ablation.

BACKGROUND: Atrial fibrillation (AF) induces functional mitral regurgitation (FMR) and tricuspid regurgitation (FTR) during atrial remodeling. FMR and FTR are associated with AF prognosis, but the effects for AF recurrence after ablation have not been determined conclusively. METHODS: Two hundred thirty nine patients who underwent AF ablation were enrolled. Forty five patients were excluded. In total, 194 patients were analyzed. FMR and FTR were assessed by echocardiography. The left atrial volume index (LAVI) was evaluated by contrast-enhanced computed tomography. RESULTS: Significant FMR and moderate FTR were observed in 15 (7.7%) and in 25 (12.9%) patients, respectively. The severity of tricuspid regurgitation (TR) significant correlated with age, NT-proBNP, and LAVI. During a 13.4 month follow-up period of, 39 patients (20.1%) demonstrated AF recurrence. In the Cox proportional-hazards model, E/e', FTR, and LAVI, were termed as predictor factors of AF recurrence (E/e'. hazard ratio [HR] = 1.117; P = 0.019, significant FTR. HR = 4.679; P = 0.041, LAVI. HR = 1.057; P = 0.003). Kaplan-Meier analysis showed that AF recurrence was more frequent in FTR compared with the nonsignificant FTR cases (log-rank, P = 0.001). Although survival analysis showed no difference with or without FMR, the presence of FMR and FTR was strongly associated with high-AF recurrence (log-rank, P = 0.004). CONCLUSIONS: AF recurrence was associated with E/e', LAVI, and extensive FTR. Specifically, the combination of FTR and FMR markedly worsens the AF prognosis.

Increased Arterial Stiffness in Chronic Thromboembolic Pulmonary Hypertension Was Improved with Riociguat and Balloon Pulmonary Angioplasty: A Case Report.

BACKGROUND: The role of arterial stiffness in the pathophysiology of chronic thromboembolic pulmonary hypertension (CTEPH) is unclear. The cardio-ankle vascular index (CAVI) is a novel arterial stiffness index reflecting stiffness of the arterial tree from the origin of the aorta to the ankle, independent from blood pressure at the time of measurement. CAVI reflects functional stiffness, due to smooth muscle cell contraction or relaxation, and organic stiffness, due to atherosclerosis. Here, we report the case of a patient with an increased CAVI due to CTEPH and the improvement after riociguat administration and balloon pulmonary angioplasty (BPA). CASE PRESENTATION: A 65-year-old man suffered from dyspnea on exertion, and he was diagnosed with distal CTEPH. The mean pulmonary artery pressure (mPAP) was 51 mmHg, and the initial CAVI was 10.0, which is high for patient's age. In addition to right ventricular dysfunction, left ventricular dysfunction was observed as reduced global longitudinal strain (GLS-LV). After riociguat administration, CAVI decreased to 9.1 and GLS-LV improved from -10.3% to -17.3%, although pulmonary hypertension remained (mPAP 41 mmHg). Subsequently, a total of five BPA sessions were performed. Six months after the final BPA, mPAP decreased to 19 mmHg and GLS-LV improved to 19.3%. The patient was symptom free and his 6-minute walk distance improved from 322 m to 510 m. CAVI markedly decreased to 5.8, which is extremely low for his age. CONCLUSION: These observations suggested that arterial stiffness as measured by CAVI was increased in CTEPH, potentially deteriorating cardiac function because of enhanced afterload. The mechanism of the increase of CAVI in this case of CTEPH was obscure; however, riociguat administration and BPA might improve the pathophysiology of CTEPH partly by decreasing CAVI.

The Association of Cardio-Ankle Vascular Index (CAVI) with Biatrial Remodeling in Atrial Fibrillation.

AIM: Arterial stiffness results in elevated left ventricular filling pressure and can promote atrial remodeling due to chronic pressure overload. However, the impact of arterial stiffness on the process of atrial remodeling in association with atrial fibrillation (AF) has not been fully evaluated. METHODS: We enrolled 237 consecutive patients diagnosed with AF who had undergone ablation; data from 213 patients were analyzed. Cardio-ankle vascular index (CAVI) was used as a marker of arterial stiffness. The left atrial (LA) and right atrial (RA) volumes were determined by computed tomography imaging; atrial conduction and voltage amplitude were evaluated using a three-dimensional electromapping system used to guide the ablation procedure. RESULT: In univariate analysis, CAVI significantly correlated with atrial structural and electrical remodeling (LA volume index, r=0.297, P=0.001; RA volume index, r=0.252, P=0.004; LA conduction velocity, r=0.254, P= 0.003; LA mean voltage, r=-0.343, P=0.001, RA mean voltage; r=-0.245, P=0.015). Multivariate regression analysis revealed that CAVI and plasma levels of N-terminal B-type natriuretic peptide were independent determinants of LA and RA remodeling, respectively. On the other hand, age and LA conduction velocity were independent variables with respect to CAVI. Age-adjusted CAVI was highest in long-standing persistent AF when compared with measures of persistent or paroxysmal AF. CONCLUSION: CAVI was closely associated with biatrial remodeling in patients diagnosed with AF. These results suggest that arterial stiffness may play a significant role with respect to disease progression.

Effect of nicorandil administration on cardiac burden and cardio-ankle vascular index after coronary intervention.

Myocardial injury is a problem associated with percutaneous coronary intervention (PCI). This study aimed to clarify the role of nicorandil administration in preventing myocardial injury. This study included patients with stable angina who underwent PCI from November 2013 to June 2016. Of 58 consecutive patients, the first 20 patients received only saline infusion after PCI (control group); the other 38 patients received a continuous intravenous infusion of nicorandil and saline after PCI (nicorandil group). Troponin I and brain natriuretic peptide (BNP) levels were measured. Vascular parameters, such as blood pressure (BP), cardiac output, cardio-ankle vascular index (CAVI), and estimated systemic vascular resistance (eSVR), were measured. Troponin I of both groups increased 12 h after PCI. Changes in BNP levels between immediately after PCI and 12 h after PCI were significantly higher in the control than in the nicorandil group (10.8 ± 44.2 vs. - 2.6 ± 14.6 pg/ml, p = 0.04). In the nicorandil group, BP, eSVR, and CAVI decreased significantly at 12 h after PCI compared with those immediately after PCI (p < 0.0001), whereas no change was observed in the control group. In a single linear analysis, the change in BP (r = 0.36, p < 0.01) and nicorandil administration (r = - 0.47, p < 0.001) was significantly correlated with the change in CAVI, multiple regression analysis revealed that the changes in CO and eSVR were significant contributing factors for the changes in CAVI. PCI could result in myocardial injury and/or cardiac burden in patients with stable angina. Nicorandil administration after PCI may be effective in relieving the burden by decreasing arterial stiffness (CAVI).

The impact of sleep apnea on right atrial structural remodeling with atrial fibrillation.

BACKGROUND: Atrial remodeling associated with atrial fibrillation (AF) and sleep apnea is well known. Although sleep apnea is known to be associated with left atrial (LA) remodeling, its association with right atrial (RA) remodeling remains unclear. The study aimed to investigate the effect of sleep apnea on RA remodeling. METHODS: We enrolled 141 AF patients who had undergone ablation. Sleep study results were evaluated using a portable sleep apnea test device. RA and LA volumes were determined by computed tomography (CT), and atrial structural remodeling was defined as atrial volume on CT≥110mL according to previous reports. The atrial substrate was evaluated by three-dimensional electroanatomical mapping. RESULTS: After excluding 30 patients who received more than one catheter ablation or who could not receive enhanced CT, 111 patients were finally analyzed. The patients were classified into four groups according to the presence of RA and/or LA enlargement. Significant differences in AF type, N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, and apnea-hypopnea index (AHI) were observed among the four groups. In univariate analysis, AHI values correlated with NT-proBNP levels (r=0.293, p=0.002), left ventricular ejection fraction (r=-0.198, p=0.044), LA volume (r=0.370, p<0.001), and RA volume (r=0.465, p<0.001). Multiple regression analysis showed that AHI was an independent predictor of increased RA volume, and LA was excluded as a multiple risk factor in AHI. AF type-adjusted AHI levels correlated with RA volume, and RA remodeling correlated with the percentage of LA low-voltage area. CONCLUSIONS: Sleep apnea was strongly associated with RA structural remodeling regardless of paroxysmal and non-paroxysmal AF, and this relationship was more prominent than the effect of LA. Our results suggest that the association between sleep apnea and RA dilatation should be given attention.

Analysis of Heart Rate Variability in a Patient with Takotsubo Cardiomyopathy Syndrome on the Actual Onset Day.

A healthy 73-year-old woman unpredictably developed Takotsubo cardiomyopathy syndrome (TTS) during Holter-electrocardiogram (ECG) recording. Thus, the complete chronological ECG data on the actual onset day of TTS were obtained. Many heart rate variability (HRV) parameters, including the low-frequency components (LF) and the high-frequency components (HF), on the actual onset day and in the healing phase were calculated. The interesting facts on the actual onset day were that the suppression of both LF and HF appeared earlier than the changes of the ECG waveform; and the LF/HF ratio remained within the normal range, although both LF and HF were markedly suppressed. The abnormality on the actual onset day was clear compared with the healing phase. It is noteworthy to obtain the chronological ECG data on the actual onset day of TTS in a healthy patient. The present data are unique in terms of being analyzed on the actual onset day. Although the HRV parameters, including LF and HF, were obviously abnormal, there is some skepticism about using HRV parameters as indices of cardiac autonomic activity. In the present case, it was concluded that the abnormality of cardiac autonomic activity contributed to the onset of TTS. These data are unlikely to ever be replicated, and we hope that this report helps elucidate the TTS mechanism.

A Case Demonstrating the Cardio-Vascular Interaction by a New Cardio-Ankle Vascular Index During the Treatment of Concentric Hypertrophy.

A 42-year-old hypertensive woman came to our hospital suffering from shortness of breath. Her left ventricular mass index (LVMI) was increased, and a new arterial stiffness index, cardio-ankle vascular index (CAVI), was also elevated. By treating hypertension (HT), diabetes mellitus (DM) and obstructive sleep apnea (OSA), her left ventricular concentric hypertrophy was improved, accompanying with a decrease in CAVI. These observations suggested that arterial stiffness monitored with CAVI might be involved in cardiac hypertrophy. This cardio-vascular interaction could be demonstrated at the first time by monitoring CAVI, which is not affected by blood pressure (BP) at measuring time.

A Case Demonstrating the Ribaroxaban Therapy for Paradoxical Embolism.

A paradoxical embolism is defined as a systemic arterial embolus due to passage of a venous thrombus through a right to left shunt. In recent years, vitamin K antagonists and aspirin are used as anticoagulant medications for the secondary prevention of paradoxical embolism. We describe a case of subacute right upper limb ischemia due to paradoxical embolism. We first started treatment with urokinase, intravenous (IV) injection and unfractionated heparin (continuous IV). As her condition and the serum D-dimer level showed improvement, we started catheterization on day 7 after admission; however the right brachial artery thrombus did not disappear. For her outpatient care, based on the viewpoint of providing rapid anticoagulation therapy within the therapeutic range, having longest periods of initial intensive therapy we chose the treatment using ribaroxaban. Recanalization of her right brachial artery was achieved with this therapy. Here, we report the effective results of initial intensive therapy using ribaroxaban for paradoxical embolism.

Congenital Absence of Left Atrial Appendage Diagnosed by Multimodality Imaging.

A 70-years-old male with a history of hypertension and drug resistant paroxysmal atrial fibrillation (AF) presented to our hospital for catheter ablation to his symptomatic AF. He had no prior surgical or percutaneous procedure to close or exclude the left atrial appendage (LAA). A transesophageal echocardiography (TEE) was performed to rule out intra-cardiac thrombus prior to the ablation procedure. Although the TEE imaging at multiple acquisition angles was obtained, the LAA could not be visualized and an absence of the LAA was suspected. An absence of the LAA was confirmed using cardiac computed tomography (CT), which included 3D reconstruction. Additionally, the LAA was not visualized with left atrium (LA) angiography. During the ablation procedure, 3D voltage mapping in LA was created and no low voltage area or abnormal potential was recorded around the usual root location of the LAA. Successful electrical pulmonary vein isolation was achieved with no major complications. After six months of follow-up, the patient remained in sinus rhythm without any antiarrhythmic drugs and showed no related clinical symptoms. He stopped his anticoagulation therapy due to lack of evidence of AF recurrence and an absence of LAA. Multimodality imaging allowed us to identify the congenital absence of LAA.

Susceptibilities of epicardial and subcutaneous fat tissue for browning-gene expression and diet-induced volume reduction are different.

The upregulation of brown or brown-like beige adipocytes is a potential strategy for the prevention or treatment of diabetes and coronary artery diseases in obese patients. Epicardial adipose tissue (EAT) differs significantly from subcutaneous fat tissue (SAT) in metabolic properties. To investigate properties of EAT further, thermogenesis gene expression was investigated in human autopsy and murine samples, and adipocytes differentiated from EAT mesenchymal cells. Subsequently, analyzed EAT volume alterations were observed to be associated with weight reduction in obese patients by imaging. Gene expression analyses of autopsy samples revealed that UCP­1 mRNA levels in EAT were significantly increased compared with SAT, and ß3­adrenergic receptor (AR) levels tended to be increased; this finding was verified in comparing EAT with SAT in mice. Browning stimulation of human EAT­derived MCs increased uncoupling protein­1 and ß3­AR levels by 3.2 fold­ and 12.6­fold compared with SAT­derived MCs, respectively. Subsequent imaging for EAT volume measurement using multi­detector computed tomography in 10 obese patients revealed that mean EAT volumes did not significantly decrease following weight loss therapy. The EAT volume alterations were not correlated with weight changes, whereas positive correlations were observed in SAT and visceral adipose tissue. Therefore, the studies in man and mouse on EAT properties demonstrated that susceptibilities of EAT and SAT for browning­gene expression and diet­induced volume reduction were grossly different. The data suggest a potential association of EAT with local thermogenetic and metabolic homeostasis in cardiac and/or cardiovascular cells, in conjunction with systemic energy metabolism.