[Efficacy of Anamorelin for the Treatment of Cancer Cachexia and Factors Associated with Weight Gain].

Cancer cachexia causes anorexia and metabolic disorders, eventually leading to sarcopenia, which in turn contributes to the development of functional disabilities. Although anamorelin hydrochloride tablets are marketed to treat cancer cachexia, their efficacy varies significantly among patients. Here, we investigated the efficacy of anamorelin and the factors associated with weight gain. The factors that contributed to weight gain in patients before starting anamorelin were as follows: the patients' disease stage had not progressed to refractory cachexia based on the cancer cachexia classification of the European Palliative Care Research Collaborative; the patients had received fewer lines of anticancer treatment at the start of oral administration of anamorelin; and the patients had not met all the criteria for starting treatment with anamorelin, namely, C-reactive protein level >0.5 mg/dL, hemoglobin level <12 g/dL, and albumin level <3.2 g/dL. These results suggest that early administration of anamorelin hydrochloride tablets may increase the response rate when cancer cachexia is diagnosed.

Relationship between the atrial-activation pattern around the triangle of Koch and successful ablation sites in slow-fast atrioventricular nodal reentrant tachycardia.

Background: The precise details of atrial activation around the triangle of Koch (ToK) remain unknown. We evaluated the relationship between the atrial-activation pattern around the ToK and success sites for slow-pathway (SP) modification ablation in slow-fast atrioventricular reentrant tachycardia (AVNRT). Methods: Thirty patients with slow-fast AVNRT who underwent successful ablation were enrolled. Atrial activation around the ToK during sinus rhythm was investigated using ultra-high-density mapping pre-ablation. The relationships among features of atrial-activation pattern and success sites were examined. Results: Of 30 patients (22 cryoablation; 8 radiofrequency ablation), 26 patients had a collision site of two wavefronts of delayed atrial activation within ToK, indicating a success site. The activation-search function of Lumipoint software, which highlights only atrial activation with a spatiotemporal consistency, showed non-highlighted area on the tricuspid-annulus side of ToK. In 23 of the patients, a spiky potential was recorded at that collision site outside the Lumipoint-highlighted area. Fifteen cryoablation patients with a success site coincident with a collision site outside the Lumipoint-highlighted area had significantly more frequent disappearances of SP after initial cryoablation (46.7% vs. 0%, p = .029), fewer cryoablations (3.7 ± 1.8 vs. 5.3 ± 1.3, p = .045), and shorter procedure times (170 ± 57 vs. 228 ± 91 min, p = .082) compared to the seven cryoablation patients without such sites. Four patients had transient AV block by ablation inside the Lumipoint-highlighted area with fractionated signals, but no patient developed permanent AV block or recurrence post-procedure (median follow-up: 375 days). Conclusions: SP modification ablation at the collision site of atrial activation of the tricuspid-annulus side along with a spiky potential could provide a better outcome.

Impact of nocturnal blood pressure dipping on recurrence of atrial fibrillation after pulmonary vein isolation.

Lack of the typical nocturnal blood pressure (BP) fall, i.e non-dipper, has been known as a cardiovascular risk. However, the influence of non-dipper on atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI) has been unclear. We investigated the clinical impact of non-dipping as evaluated by 24-hour ambulatory BP monitoring on the long-term outcome of AF recurrence post-PVI in 76 AF patients with a history of increased BP. The PVI procedure was successful in all 76 patients (mean age, 66±9years; antihypertensive medication, 89%; non-paroxysmal AF, 24%). Twenty patients had AF recurrence during a median follow-up of 1138 days. There was no difference in BP levels between the AF recurrence and non-recurrence groups (average 24 h systolic BP:126 ± 17 vs.125 ± 14 mmHg; P = 0.84). On the other hand, the patients with non-dipper had a higher AF recurrence than those with dipper (38.9% vs.15.0%; P = 0.018). In Cox hazard analysis adjusted by age, non-paroxysmal AF and average 24-hr systolic BP level, the non-dipper was an independent predictor of AF recurrence (HR 2.78 [95%CI:1.05-7.34], P = 0.039). Non-dipper patients had a larger left atrial (LA) volume index than the dipper patients (45.9 ± 17.3 vs.38.3 ± 10.2 ml/m2, P = 0.037). Among the 58 patients who underwent high-density voltage mapping in LA, 11 patients had a low-voltage area (LVA) defined as an area with a bipolar voltage < 0.5 mV. However, there was no association of LVA with non-dipper or dipper (22.2% vs.16.1%, P = 0.555). Non-dipper is an independent predictor of AF recurrence post-PVI. Management of abnormal diurnal BP variation post-PVI may be important.

Metabolomic Profiling of Mice with Tacrolimus-Induced Nephrotoxicity: Carnitine Deficiency in Renal Tissue.

Tacrolimus (TAC)-induced chronic nephrotoxicity (TAC nephrotoxicity) has a detrimental effect on long-term kidney graft survival. However, the pathogenesis of TAC nephrotoxicity remains largely unknown. We explored it by focusing on metabolic changes in renal tissues. In this study, mice were separated into TAC and control groups (n = 5/group). TAC was administered to the TAC group (1 mg/kg/d for 28 days) subcutaneously. The control group was similarly treated with normal saline. Renal tissue metabolomes were evaluated. Renal fibrosis was observed only in the TAC group. Metabolomic analysis showed that carnitine and related metabolites were substantially lower in the TAC group than in the control group, presumably due to impaired biosynthesis and reabsorption. Low carnitine levels impair antioxidation in renal tissues and ß-oxidation in mitochondria, which may lead to renal tissue damage. This metabolomic analysis revealed that carnitine deficiency in renal tissue appears to explain TAC nephrotoxicity.

A mutually communicable external system resource in remote monitoring for cardiovascular implantable electronic devices.

BACKGROUND: Using third-party resources to manage remote monitoring (RM) data from implantable cardiac electronic devices (CIEDs) can assist in device clinic workflows. However, each hospital-acquired data is not used for further analysis as big data. METHODS AND RESULTS: We developed a real-time and automatically centralized system of CIED information from multiple hospitals. If the extensive data-based analysis suggests individual problems, it can be returned to each hospital. To show its feasibility, we prospectively analyzed data from six hospitals. For example, unexpected abnormal battery levels were easily illustrated without recall information. CONCLUSIONS: The centralized RM system could be a new platform that promotes the utilization of device data as big data, and that information could be used for each patient's practice.

BNP level predicts bleeding event in patients with heart failure after percutaneous coronary intervention.

OBJECTIVE: This study aimed to investigate the association between heart failure (HF) severity measured based on brain natriuretic peptide (BNP) levels and future bleeding events after percutaneous coronary intervention (PCI). BACKGROUND: The Academic Research Consortium for High Bleeding Risk presents a bleeding risk assessment for antithrombotic therapy in patients after PCI. HF is a risk factor for bleeding in Japanese patients. METHODS: Using an electronic medical record-based database with seven tertiary hospitals in Japan, this retrospective study included 7160 patients who underwent PCI between April 2014 and March 2020 and who completed a 3-year follow-up and were divided into three groups: no HF, HF with high BNP level and HF with low BNP level. The primary outcome was bleeding events according to the Global Use of Streptokinase and t-PA for Occluded Coronary Arteries classification of moderate and severe bleeding. The secondary outcome was major adverse cardiovascular events (MACE). Furthermore, thrombogenicity was measured using the Total Thrombus-Formation Analysis System (T-TAS) in 536 consecutive patients undergoing PCI between August 2013 and March 2017 at Kumamoto University Hospital. RESULTS: Multivariate Cox regression showed that HF with high BNP level was significantly associated with bleeding events, MACE and all-cause death. In the T-TAS measurement, the thrombogenicity was lower in patients with HF with high BNP levels than in those without HF and with HF with low BNP levels. CONCLUSIONS: HF with high BNP level is associated with future bleeding events, suggesting that bleeding risk might differ depending on HF severity.

Multi-Omics of Familial Thoracic Aortic Aneurysm and Dissection: Calcium Transport Impairment Predisposes Aortas to Dissection.

Several genetic defects, including a mutation in myosin heavy chain 11 (Myh11), are reported to cause familial thoracic aortic aneurysm and dissection (FTAAD). We recently showed that mice lacking K1256 of Myh11 developed aortic dissection when stimulated with angiotensin II, despite the absence of major pathological phenotypic abnormalities prior to stimulation. In this study, we used a comprehensive, data-driven, unbiased, multi-omics approach to find underlying changes in transcription and metabolism that predispose the aorta to dissection in mice harboring the Myh11 K1256del mutation. Pathway analysis of transcriptomes showed that genes involved in membrane transport were downregulated in homozygous mutant (Myh11ΔK/ΔK) aortas. Furthermore, expanding the analysis with metabolomics showed that two mechanisms that raise the cytosolic Ca2+ concentration-multiple calcium channel expression and ADP-ribose synthesis-were attenuated in Myh11ΔK/ΔK aortas. We suggest that the impairment of the Ca2+ influx attenuates aortic contraction and that suboptimal contraction predisposes the aorta to dissection.

Comparison of heart rate and cardiac output of VVI pacemaker settings in patients with atrial fibrillation with bradycardia.

Background: While most VVI pacemakers in bradycardic patients are set to a low limit of 60/min, the optimal lower limit rate for VVI pacemakers in atrial fibrillation has not been established. Although an increase in heart rate within the normal range in the setting of a VVI pacemaker might be expected to lead to an increase in cardiac output with the shortening of the diastolic time, the changes in cardiac output at different pacemaker settings have not been fully clarified. Methods: We included 11 patients with bradycardic atrial fibrillation who had VVI pacemakers implanted. Stroke volume was measured using the electrical cardiometry method (AESCULONⓇ mini; Osypka Medical) without pacing and at ventricular pacings of 60, 70, 80, and 90/min. Results: Stroke volume decreased stepwise at ventricular pacing rates of 60, 70, 80, and 90/min (63.6 ± 11.2, 61.9 ± 10.6, 59.3 ± 12.2, and 57.5 ± 12.2 mL, p < .001), but cardiac output increased (3.81 ± 0.67, 4.33 ± 0.74, 4.74 ± 0.97, and 5.17 ± 1.09 L/min, p < .001). The rate of increase in cardiac output at a pacing rate of 70/min compared to 60/min correlated with left ventricular end-systolic volume (r = 0.711, p = .014). Conclusions: Cardiac output increased at a pacing rate of 70 compared to 60 in bradycardic atrial fibrillation patients, and the rate of increase in cardiac output was greater in those with larger left ventricular end-systolic volume.

Unipolar-voltage-based evaluation of left atrial tissue properties and ablation outcome in patients with atrial fibrillation.

AIMS: The relationship between local unipolar voltage (UV) in the pulmonary vein (PV)-ostia and left atrial wall thickness (LAWT) and the utility of these parameters as indices of outcome after atrial fibrillation (AF) ablation remain unclear. METHODS AND RESULTS: Two-hundred seventy-two AF patients who underwent AF ablation were enrolled. Unipolar voltage of PV-ostia was measured using a CARTO system, and LAWT was measured using computed tomography. The primary endpoint was atrial tachyarrhythmia (ATA) recurrence including AF. The ATA recurrence was documented in 74 patients (ATA-Rec group). The UV and LAWT of the bilateral superior PV roof to posterior and around the right-inferior PV in the ATA-Rec group were significantly greater than in patients without ATA recurrence (ATA-Free group) (P < 0.001). The UV had a strong positive correlation with LAWT (R2 = 0.446, P < 0.001). The UV 2.7 mV and the corresponding LAWT 1.6 mm were determined as the cut-off values for ATA recurrence (P < 0.001, respectively). Multisite LA high UV (HUV, ≥4 areas of >2.7 mV) or multisite LA wall thickening (≥5 areas of >1.6 mm), defined as LA hypertrophy (LAH), was related to higher ATA recurrence. Among 92 LAH patients, 66 had HUV (LAH-HUV) and the remaining 26 had low UV (LAH-LUV), characterized by history of non-paroxysmal AF and heart failure, reduced LV ejection fraction, or enlarged LA. In addition, LAH-LUV showed the worst ablation outcome, followed by LAH-HUV and No LAH (log-rank P < 0.001). CONCLUSION: Combining UV and LAWT enables us to stratify recurrence risk and suggest a tailored ablation strategy according to LA tissue properties.

Impact of heart failure severity and major bleeding events after percutaneous coronary intervention on subsequent major adverse cardiac events.

Background: Heart failure (HF) is associated with a high bleeding risk after percutaneous coronary intervention (PCI). Additionally, major bleeding events increase the risk of subsequent major adverse cardiac events (MACE). However, whether brain natriuretic peptide (BNP) levels and major bleeding events following PCI are associated with MACE and all-cause death remains unknown. This study aimed to investigate the impact of HF severity or bleeding on subsequent MACE and all-cause death. Methods: The Clinical Deep Data Accumulation System (CLIDAS), a multicenter database involving seven hospitals in Japan, was developed to collect data from electronic medical records. This retrospective analysis included 7160 patients who underwent PCI between April 2014 and March 2020 and completed a three-year follow-up. Patients were divided according to the presence of HF with high BNP (HFhBNP) (>100 pg/ml) and major bleeding events within 30 days post-PCI (30-day bleeding): HFhBNP with bleeding (n = 14), HFhBNP without bleeding (n = 370), non-HFhBNP with bleeding (n = 74), and non-HFhBNP without bleeding (n = 6702). Results: In patients without 30-day bleeding, HFhBNP was a risk factor for MACE (hazard ratio, 2.19; 95% confidence interval, 1.56-3.07) and all-cause death (hazard ratio, 1.60; 95% confidence interval, 1.60-2.23). Among HFhBNP patients, MACE incidence was higher in patients with 30-day bleeding than in those without bleeding, but the difference was not significant (p = 0.075). The incidence of all-cause death was higher in patients with bleeding (p = 0.001). Conclusions: HF with high BNP and bleeding events in the early stage after PCI might be associated with subsequent MACE and all-cause death.

[Efficacy and Safety of Trastuzumab Biosimilars in Combination with Pertuzumab].

Although trastuzumab biosimilars have been approved based on clinical studies on their use as monotherapy or in combination with chemotherapy, clinical studies on their combination with pertuzumab are lacking. Data on the efficacy and safety of this combination are scarce. We evaluated the efficacy and safety of trastuzumab biosimilars in combination with pertuzumab. Progression-free survival was 10.5 months(95% confidence interval[CI]: 3.3-16.3)for a reference biological product and 8.7 months(2.1-not applicable)for biosimilars with a hazard ratio of 0.96(95%CI: 0.29-3.13, p=0.94); however, no statistically significant difference was observed. The incidence of adverse events was not significantly different between the reference biological product and biosimilars, and no increase was observed for any adverse events after switching to the biosimilars. The results of this study verify that a combination of trastuzumab biosimilars with pertuzumab is sufficiently effective and safe in clinical practice.

Dramatically Improved Severe Pulmonary Arterial Hypertension Caused by Qing-Dai (Chinese Herbal Drug) for Ulcerative Colitis.

Pulmonary arterial hypertension (PAH) is a rare and fatal disease for which some causative drugs have been developed. Qing-Dai is a Chinese herbal drug that is sometimes used as a specific treatment for ulcerative colitis in Asia, including Japan. Here, we report a case of severe Qing-Dai-induced PAH. A 19-year-old woman who has been taking Qing-Dai for 8 months was admitted for exertional dyspnea. Her mean pulmonary artery pressure dramatically improved from 72 to 18 mmHg with Qing-Dai discontinuation and PAH-specific therapy. After 6 years of onset, she had not relapsed with PAH with PAH-specific therapy.

Impact of unipolar voltage criteria for left atrial posterior wall on atrial fibrillation recurrence after pulmonary vein isolation.

INTRODUCTION: Beyond pulmonary vein isolation (PVI), additional therapeutic strategies for atrial fibrillation (AF) have not been established. Remodeling of the left atrium (LA) could impact AF recurrence post-PVI. We investigated the impact of unipolar voltage (UV) criteria for the LA posterior wall (LA-PW) on AF recurrence post-PVI. METHODS: We reviewed the cases of 106 AF patients (mean age 63.8 years, nonparoxysmal AF: 59%) who underwent extensive encircling PVI by radiofrequency ablation guided by a 3-dimension mapping system, investigating the impact on AF recurrence of the UV criteria of the LA. RESULTS: Out of all patients, 26 patients had AF recurrence during post-PVI follow-up [median 603 days]. They showed a higher percentage of nonparoxysmal AF (80.8 vs. 52.5%, p = .011), longer AF duration (2.9 ± 2.7 vs. 1.0 ± 1.7 years, p = .002), and larger area size of UV < 2.0 mV in LA-PW (2.8 ± 1.8 vs. 1.0 ± 1.5 cm2 , p < .001) than those without recurrence. Cox Hazard analysis for AF recurrence adjusted by age, gender, AF duration, body mass index and left atrial volume index revealed that an area size over 2.0 cm2 of UV < 2.0 mV in LA-PW (HR 6.9 [95% CI:1.3-35.5], p = .021) posed independent risks for AF recurrence post-PVI. The atrial arrhythmia-free survival rate was higher in those with no area of UV < 3.0 mV in LA-PW compared to those with a sizable area (>2.0 cm2 ) of UV < 3.0 mV and <2.0 mV (95.0% vs. 74.2% vs. 57.1%, Log-Rank: p < .001). In the AF etiology of patients with AF recurrence, 9 of 14 patients who underwent the 2nd procedure had no PV reconnection, and 8 patients required the LA-PW isolation for their non-PV AF. CONCLUSION: UV criteria of LA-PW is a useful parameter for AF-recurrence post-PVI. Lower UV in LA-PW as an indication of electrical remodeling could indicate a higher risk of AF recurrence and the need for further therapeutic strategies.

Syncope after COVID-19 Vaccination in a Young Man with Unmasking Brugada Syndrome.

A 23-year-old man with no significant medical history was rushed to a hospital due to transient loss of consciousness with incontinence. The patient had developed a fever after his second dose of coronavirus disease 2019 (COVID-19) vaccine, and the patient was found groaning in bed approximately 40 hours after the vaccination in the early morning. The patient was diagnosed with Brugada syndrome (BrS) based on a drug-provocation test. His father had been diagnosed with BrS and died suddenly at 51 years of age. Young adults with a family history of BrS should be cautioned about fever following COVID-19 vaccination.

Sex Differences in Long-Term Outcomes in Patients With Chronic Coronary Syndrome After Percutaneous Coronary Intervention　- Insights From a Japanese Real-World Database Using a Storage System.

BACKGROUND: Several studies have reported some sex differences in patients with coronary artery diseases. However, the results regarding long-term outcomes in patients with chronic coronary syndrome (CCS) are inconsistent. Therefore, the present study investigated sex differences in long-term outcomes in patients with CCS after percutaneous coronary intervention (PCI).Methods and Results: This was a retrospective, multicenter cohort study. We enrolled patients with CCS who underwent PCI between April 2013 and March 2019 using the Clinical Deep Data Accumulation System (CLIDAS) database. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, or hospitalization for heart failure. In all, 5,555 patients with CCS after PCI were included in the analysis (4,354 (78.4%) men, 1,201 (21.6%) women). The median follow-up duration was 917 days (interquartile range 312-1,508 days). The incidence of MACE was not significantly different between the 2 groups (hazard ratio [HR] 1.20; 95% confidential interval [CI] 0.97-1.47; log-rank P=0.087). After performing multivariable Cox regression analyses on 4 different models, there were still no differences in the incidence of MACE between women and men. CONCLUSIONS: There were no significant sex differences in MACE in patients with CCS who underwent PCI and underwent multidisciplinary treatments.

Relationships Among Heart Rate, ß-Blocker Dosage, and Prognosis in Patients With Coronary Artery Disease in a Real-World Database Using a Multimodal Data Acquisition System.

BACKGROUND: The optimal heart rate (HR) and optimal dose of ß-blockers (BBs) in patients with coronary artery disease (CAD) have been unclear. We sought to clarify the relationships among HR, BB dose, and prognosis in patients with CAD using a multimodal data acquisition system.Methods and Results: We evaluated the data for 8,744 CAD patients who underwent cardiac catheterization from 6 university hospitals and the National Cerebral and Cardiovascular Center and who were registered using the Clinical Deep Data Accumulation System. Patients were divided into quartile groups based on their HR at discharge: Q1 (HR <60 beats/min), Q2 (HR 60-66 beats/min), Q3 (HR 67-74 beats/min), and Q4 (HR ≥75 beats/min). Among patients with acute coronary syndrome (ACS) and patients with chronic coronary syndrome (CCS), those in Q4 (HR ≥75 beats/min) had a significantly greater incidence of major adverse cardiac and cerebral events (MACCE) compared with those in Q1 (ACS patients: hazard ratio 1.65, P=0.001; CCS patients: hazard ratio 1.45, P=0.019). Regarding the use of BBs (n=4,964), low-dose administration was significantly associated with MACCE in the ACS group (hazard ratio 1.41, P=0.012), but not in patients with CCS after adjustment for covariates. CONCLUSIONS: HR ≥75 beats/min was associated with worse outcomes in patients with CCS or ACS.

Electrogram characteristics at successful cryoablation sites in slow-fast atrioventricular nodal reentrant tachycardia.

PURPOSE: Cryoablation is a safe alternative to radiofrequency (RF) ablation for slow-fast atrioventricular reentrant tachycardia (AVNRT); however, optimal electrogram parameters for site selection remain unknown. We retrospectively investigated local electrograms for slow pathway (SP) modification in cryoablation. METHODS: Forty-five consecutive patients with slow-fast AVNRT who underwent cryoablation using a 6-mm-tip catheter were enrolled. Electrogram parameters for sites of successful SP modification (success-sites) were investigated; these included the interval between atrial activation at His and the last deflection of SP potential, defined as the His(A)-SPP interval. In 8 patients, 3-dimensional mapping by multi-electrode catheter was performed pre-ablation for more detailed SP assessment. RESULTS: Twenty-seven of 45 patients had successful SP modification by 1 cycle of freeze-thaw-freeze cryoablation at a single site with a low amplitude and fragmented SP potential. Among a total of 76 cryoablation sites in all patients, the His(A)-SPP interval at success-sites (45 sites) was significantly longer than that at unsuccess-sites (31 sites) (86 ± 9 vs.78 ± 10 msec, p < 0.0001). The AV amplitude ratio was not significantly different between success-and unsuccess-sites (0.21 ± 0.22 vs.0.25 ± 0.23, p = 0.429). The cutoff value of the His(A)-SPP interval for successful cryoablation was 82 msec with a sensitivity of 0.67 and specificity of 0.71 (AUC: 0.739; 95%CI: 0.626-0.852; p < 0.0001). Three-dimensional mapping in all 8 patients showed that sites with the most delayed atrial activation and the last deflection of the fragmented SP potential within the Koch's triangle coincided with success-sites. CONCLUSION: A longer His(A)-SPP interval and fractionated SP potential were characteristics of successful cryoablation for SP modification in slow-fast AVNRT.