Publications by authors named "Hiroshi Tada"

332 Publications

Ultra-high resolution mapping of reverse typical atrial flutter: electrophysiological properties of a right atrial posterior wall and interatrial septum activation pattern.

J Interv Card Electrophysiol 2021 May 8. Epub 2021 May 8.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Shimo-aiduki, Matsuoka, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.

Purpose: We aimed to elucidate the right atrial posterior wall (RAPW) and interatrial septum (IAS) conduction pattern during reverse typical atrial flutter (clockwise AFL: CW-AFL).

Methods: This study included 30 patients who underwent catheter ablation of CW-AFL (n = 11) and counter-clockwise AFL (CCW-AFL; n = 19) using an ultra-high resolution mapping system. RAPW transverse conduction block was evaluated by the conduction pattern on propagation maps and double potentials separated by an isoelectric line. The degree of blockade was evaluated by the %blockade, which was calculated by the length of the blocked area divided by the RAPW length. IAS activation patterns were also investigated dependent on the propagation map.

Results: The average %blockade of the RAPW was significantly smaller in patients with CW-AFL than those with CCW-AFL (25 [3-74]% vs. 67 [57-75]%, p < 0.05). CW-AFL patients exhibited 3 different RAPW conduction patterns: (1) a complete blockade pattern (3 patients), (2) moderate (> 25% blockade) blockade pattern (2 patients), and (3) little (< 25% blockade) blockade pattern (6 patients). In contrast, the little blockade pattern was not observed in CCW-AFL patients. Of 11 CW-AFL patients, 4, including all patients with an RAPW complete blockade pattern, had an IAS activation from the wavefront from the anterior tricuspid annulus (TA), and 6 had an IAS activation from the wavefronts from both the anterior TA and RAPW. One patient had IAS activation dominantly from the wavefront from the RAPW.

Conclusions: RAPW transverse conduction blockade during CW-AFL was less frequent than during CCW-AFL, which possibly caused various IAS activation patterns.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10840-021-01003-0DOI Listing
May 2021

The anti-angiogenic agent lenvatinib induces tumor vessel normalization and enhances radiosensitivity in hepatocellular tumors.

Med Oncol 2021 Apr 21;38(6):60. Epub 2021 Apr 21.

Department of Medical Physics, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.

The evaluation of angiogenesis inhibitors requires the analysis of the precise structure and function of tumor vessels. The anti-angiogenic agents lenvatinib and sorafenib are multi-target tyrosine kinase inhibitors that have been approved for the treatment of hepatocellular carcinoma (HCC). However, the different effects on tumor vasculature between lenvatinib and sorafenib are not well understood. In this study, we analyzed the effects of both drugs on vascular structure and function, including vascular normalization, and investigated whether the normalization had a positive effect on a combination therapy with the drugs and radiation using micro X-ray computed tomography with gold nanoparticles as a contrast agent, as well as immunohistochemical analysis and interstitial fluid pressure (IFP) measurement. In mice subcutaneously transplanted with mouse HCC cells, treatment with lenvatinib or sorafenib for 14 days inhibited tumor growth and reduced the tumor vessel volume density. However, analysis of integrated data on vessel density, rates of pericyte-covering and perfused vessels, tumor hypoxia, and IFP measured 4 days after drug treatment showed that treatment with 3 mg/kg of lenvatinib significantly reduced the microvessel density and normalized tumor vessels compared to treatment with 50 mg/kg of sorafenib. These results showed that lenvatinib induced vascular normalization and improved the intratumoral microenvironment in HCC tumors earlier and more effectively than sorafenib. Moreover, such changes increased the radiosensitivity of tumors and enhanced the effect of lenvatinib and radiation combination therapy, suggesting that this combination therapy is a powerful potential application against HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12032-021-01503-zDOI Listing
April 2021

DDD mode-switching and loss of atrioventricular synchrony evokes heart failure: A rare but possible trigger of pacing-induced cardiomyopathy.

J Cardiol Cases 2021 Apr 21;23(4):158-162. Epub 2020 Nov 21.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Japan.

Pacing-induced cardiomyopathy (PICM), defined as left ventricular dysfunction, occurs in the setting of chronic, high burden right ventricular pacing. We describe an unusual case of PICM. A 64-year-old man underwent a medical check-up and was diagnosed with complete atrioventricular block (AVB) with regular and slow ventricular contractions at 38 beats/min (bpm). The patient underwent a pacemaker implantation with a dual-chamber pacing (DDD) pacemaker. This patient had no symptoms or signs of PICM during complete AVB or the period after undergoing dual-chamber pacing. However, PICM developed within a short time after the onset of atrial flutter (AFL). During AFL, the automatic mode switch of the DDD pacemaker to the DDIR mode worked normally, and the ventricles were paced with a stable and regular rate (60 bpm). Despite the administration of ß-blockers and diuretics, his symptoms and status did not improve. After the elimination of the AFL and restoration of AV synchrony with a DDD mode by catheter ablation, the deteriorated condition rapidly improved. In this patient, the coexistence of the loss of AV synchrony and high burden RV pacing during AFL might have caused this unusual PICM. Learning objective: Even when patients have no symptoms or signs of pacing-induced cardiomyopathy (PICM) during complete atrioventricular block or the period after undergoing dual-chamber pacing, automatic mode-switching to the DDI mode during atrial tachyarrhythmias could rapidly cause PICM. PICM could occur with a much more rapid time course than the historical model of PICM where cardiomyopathy may take several years to develop. Much attention should be paid during the follow-up to patients receiving DDD pacemakers to avoid any unusual PICM as in this case.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jccase.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020067PMC
April 2021

Establishment of an analytical method for simultaneous quantitation of CDK4/6 inhibitors, aromatase inhibitors, and an estrogen receptor antagonist in human plasma using LC-ESI-MS/MS.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Mar 22;1173:122655. Epub 2021 Mar 22.

Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan. Electronic address:

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors (palbociclib, abemaciclib, and ribociclib) are used to treat human epithelial growth factor receptor (HER)-2 negative and hormone receptor (HR) positive advanced breast cancer in combination with aromatase inhibitors (letrozole, anastrozole) or an estrogen receptor antagonist (fulvestrant). Administration of these drugs frequently causes severe side effects, such as neutropenia and diarrhea. Therefore, therapeutic drug monitoring (TDM) of CDK4/6 inhibitors, aromatase inhibitors, and the estrogen receptor antagonist is considered important for ensuring the efficacy and safety of these drugs. In this study, we describe a simple, highly sensitive, and specific liquid chromatography/electrospray ionization tandem mass spectrometry method for simultaneous quantitation of the concentrations of palbociclib, abemaciclib, ribociclib, letrozole, anastrozole, and fulvestrant. In addition, we analyzed plasma samples from patients with HER2-negative and HR-positive advanced breast cancer treated with these compounds using this novel method. In our method, the intra-assay relative error (RE) values ranged from -12.8% to 12.9%, the inter-assay RE values ranged from -4.8% to 6.2%, and the coefficient of variation (CV) values for intra- and inter-assay were ≤8.6% and ≤13.3%, respectively. The analytes showed good stability with RE values ranging from -13.5% to 13.6% and CV values <10.4%. Moreover, all the samples from patients were successfully quantified, and were within the range of measurement. This method can be used for TDM of routine anticancer drugs in clinical practice and for pharmacokinetics/pharmacodynamics research in future studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jchromb.2021.122655DOI Listing
March 2021

Cardiac rehabilitation after catheter ablation of atrial fibrillation in patients with left ventricular dysfunction.

Heart Vessels 2021 Apr 3. Epub 2021 Apr 3.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.

Few studies have examined the efficacy and safety of cardiac rehabilitation in patients with atrial fibrillation (AF) who underwent AF ablation. We explored the feasibility of additional cardiac rehabilitation after AF ablation in patients with a reduced left ventricular ejection fraction (LVEF). Fifty-four patients with heart failure (HF) and a reduced LVEF (HFrEF) (LVEF < 50%; 67.1 ± 11.6 years; 43 men) who underwent initial AF ablation procedures were included. Fourteen (25.9%) patients underwent cardiac rehabilitation (rehabilitation-group) and the remaining 40 (74.1%) did not (non-rehabilitation-group) after the procedure. The rehabilitation-group patients were relatively older, more likely female (p = 0.024), and had more likely a history of an HF hospitalization (p < 0.01) and cardiac device implantation (p = 0.041). The baseline LVEF was significantly lower (p = 0.043) and brain natriuretic peptide (BNP) (p < 0.01) and C-reactive protein (CRP) (p < 0.01) values were significantly higher in the rehabilitation-group. The 6-min walk distance significantly improved after 21.4 ± 11.5 days of cardiac rehabilitation during hospitalization (226.1 ± 155.9 vs. 398.1 ± 77.5 m, p = 0.016) without any adverse events. During an 18.9 ± 6.3 month follow-up period, the freedom from AF recurrence (p = 0.52) and re-hospitalizations due to HF (p = 0.63) were similar between the 2 groups. No death or strokes were observed. During the follow-up period, the LVEF significantly improved similarly in both groups, and the change in the BNP and CRP values significantly decreased in the rehabilitation-group. Despite the rehabilitation-group patients having a more severe HF status, the clinical outcomes and AF freedom were similar between the 2 groups, suggesting the favorable impact of cardiac rehabilitation after AF ablation in HFrEF patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00380-021-01829-8DOI Listing
April 2021

Superior vena cava isolation using a novel ablation catheter incorporating local impedance monitoring.

J Interv Card Electrophysiol 2021 Mar 23. Epub 2021 Mar 23.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Shimo-aiduki, Matsuoka, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.

Background: A novel technology able to measure the local impedance (LI) during radiofrequency ablation has become available for clinical use. We investigated the change in the LI characteristics during superior vena cava isolations (SVCIs) using a novel catheter equipped with mini-electrodes.

Methods: Twenty paroxysmal atrial fibrillation patients (68 ± 9 years; 14 males) underwent an SVCI by targeting breakthroughs. Subsequently, dormant conduction provoked by adenosine triphosphate (ATP) was evaluated.

Results: Electrical SVCIs were successfully achieved in all with 7.2 ± 3.0 radiofrequency applications (RFA) without any complications. The procedure and fluoroscopic times were 13.1 ± 8.1 and 2.8 ± 2.3 min. No ablation was required at the anteroseptal SVC in 19 (95.0%) patients. The baseline LI and generator impedance (GI) were 125 ± 23 and 105 ± 14Ω. LI drops during RFA were significantly greater than GI drops (17 ± 12 vs. 4 ± 4Ω, p < 0.001). The correlation between the LI drops and GI drops was relatively high (R = 0.69, p < 0.001). LI drops were highest at the septal SVC and lowest at the lateral followed by antero-lateral SVC. The baseline electrogram amplitude between the mini-electrodes and tip-ring electrodes was 1.2 ± 1.4 and 0.8 ± 0.6 mV. The mini-electrode amplitude is more sharply attenuated with a greater magnitude than the tip-ring amplitude (p < 0.001). ATP-provoked dormant conduction was exposed in 10/17 (58.8%) patients and antero-lateral SVC gap locations in 7. Antero-lateral SVC LI drops were similar between patients with and without dormancy.

Conclusions: The LI drop magnitude during RFA significantly differed among the SVC segments. Antero-lateral SVC ATP-provoked dormant conduction was often exposed, and additional applications are recommended following the isolation for a robust SVCI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10840-021-00980-6DOI Listing
March 2021

The mechanisms of left septal and anterior wall reentrant atrial tachycardias analyzed with ultrahigh resolution mapping: The role of functional block in the circuit.

J Cardiovasc Electrophysiol 2021 May 17;32(5):1305-1319. Epub 2021 Mar 17.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.

Background: Low voltage areas (LVAs) are most commonly observed on the left atrial (LA) septal/anterior wall.

Objective: We explored the mechanisms of LA septal/anterior wall reentrant tachycardias (LASARTs) using ultrahigh resolution mapping.

Methods: This study included seven consecutive LASARTs in six patients (75 [62.2-82.8] years, 4 women) who underwent atrial tachycardia (AT) mapping and ablation using Rhythmia systems.

Results: The AT cycle length was 266 (239-321) ms. During ATs, 11.0 (9.0-12.9) cm of LVAs were identified in all, and 0.8 (0.7-1.7) cm of dense scar was identified in four patients. Five ATs rotated around dense scar, while two rotated around functional linear block, which was confirmed during atrial pacing after AT termination. The AT circuit length was 8.7 ± 2.1 cm with a conduction velocity of 30.4 ± 3.7 cm/s. A median of 3.0 (2.0-4.0) slow conduction areas per circuit were identified, and 17/23 (73.9%) areas were present in LVAs, while they were at the border of the LVA and normal voltage areas in the remaining 6/23 (26.1%). Global activation histograms facilitated the identification of the critical isthmus in all. Tailor-made ablation at critical isthmuses successfully eliminated all ATs. However, one patient with AT related to functional linear block experienced recurrent AT related to dense scar, which progressed after the procedure. During a mean 14 ± 13 month follow-up after the last procedure, no patients experienced recurrent ATs without any complications.

Conclusion: LASARTs consist of not only fixed conduction blocks but also functional conduction blocks. Ultrahigh resolution mapping is highly useful to decide the optimal tailor-made ablation strategy based on the mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jce.14983DOI Listing
May 2021

Real-World Safety Profile of Atrial Fibrillation Ablation Using a Second-Generation Cryoballoon in Japan: Insight From a Large Multicenter Observational Study.

JACC Clin Electrophysiol 2021 Feb 19. Epub 2021 Feb 19.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.

Objectives: This study sought to investigate the incidence and characteristics of the real-world safety profile of second-generation cryoballoon ablation (2nd-CBA) in Japan.

Background: Pulmonary vein isolation using second-generation cryoballoons is an accepted atrial fibrillation ablation strategy.

Methods: This multicenter observational study included 4,173 patients with atrial fibrillation (3,807 paroxysmal) who underwent a 2nd-CBA in 18 participating centers. The baseline data and details of all procedure-related complications within 3 months post-procedure in consecutive patients from the first case at each center were retrospectively collected.

Results: Adjunctive ablation after the pulmonary vein isolation was performed in 2,745 (65.8%) patients. Complications associated with the entire procedure were observed in 206 (4.9%) total patients, and in the multivariate analysis, the age (odds ratio: 1.015; 95% confidence interval: 1.001 to 1.030; p = 0.035) and study period were predictors. Air embolisms manifesting as ST-segment elevation and cardiac tamponade requiring drainage occurred in 63 (1.5%) and 15 (0.36%) patients, respectively. Six (0.14%) patients had strokes/transient ischemic attacks, among whom 5 underwent ablation under an interrupted anticoagulation regimen. No atrioesophageal fistulae occurred; however, 10 (0.24%) patients had symptomatic gastric hypomotility. Esophageal temperature monitoring did not reduce the incidence, and the incidence was significantly higher in patients with adjunctive posterior wall isolations or mitral isthmus ablation than those without (p = 0.004). Phrenic nerve injury occurred during the 2nd-CBA in 58 (1.4%) patients; however, all were asymptomatic and recovered within 13 months. One patient died of aspiration pneumonia.

Conclusions: This study had a high safety profile of 2nd-CBA despite including the early experience and high rate of adjunctive ablation. Care should be taken for air embolisms during 2nd-CBA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacep.2020.11.016DOI Listing
February 2021

Impact of Medical Castration on Malignant Arrhythmias in Patients With Prostate Cancer.

J Am Heart Assoc 2021 Feb 18;10(5):e017267. Epub 2021 Feb 18.

Department of Cardiovascular Medicine Faculty of Medical Science University of Fukui Japan.

Background Medical castration, gonadotropin-releasing hormone agonists, and antiandrogens have been widely applied as a treatment for prostate cancer. Sex steroid hormones influence cardiac ion channels. However, few studies have examined the proarrhythmic properties of medical castration. Methods and Results This study included 149 patients who underwent medical castration using gonadotropin-releasing hormones with/without antiandrogen for prostate cancer. The changes in the ECG findings during the therapy and associations of the electrocardiographic findings with malignant arrhythmias were studied. The QT and corrected QT (QTc) intervals prolonged during the therapy compared with baseline (QT, 394±32 to 406±39 ms [<0.001]; QTc, 416±27 to 439±31 ms [<0.001]). The QTc interval was prolonged in 119 (79.9%) patients during the therapy compared with baseline. In 2 (1.3%) patients who had no structural heart disease, torsade de pointes (TdP) and ventricular fibrillation (VF) occurred ≥6 months after starting the therapy. In patients with TdP/VF, the increase in the QTc interval from the pretreatment value was >80 ms. However, in patients without TdP/VF, the prevalence of an increase in the QTc interval from the pretreatment value of >50 ms was 11%, and an increase in the QTc interval from the pretreatment value >80 ms was found in only 4 (3%) patients. Conclusions Medical castration prolongs the QT/QTc intervals in most patients with prostate cancer, and it could cause TdP/VFs even in patients with no risk of QT prolongation before the therapy. An increase in the QTc interval from the pretreatment value >50 ms might become a predictor of TdP/VF. Much attention should be paid to the QTc interval throughout all periods of medical castration to prevent malignant arrhythmias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.120.017267DOI Listing
February 2021

[Supporting Technology for Development of Antibody Drug and Diagnostic Method to Predict Response to the Drug, by Using Fluorescence Imaging].

Gan To Kagaku Ryoho 2021 Feb;48(2):170-175

Dept. of Medical Physics, Graduate School of Medicine, Tohoku University.

Fluorescence imaging is a very useful method for visualizing molecules and cells, but when tissues are measured", decrease in resolution due to increased scattering and absorption of light in proportion to tissue thickness (problem 1)" and "decrease in signal to noise(S/N)ratio of positive signal due to tissue autofluorescence(problem 2)"are problems to be solved. In this paper, to develop a technology to improve the analysis accuracy of drug efficacy mechanisms in preclinical trial of drug discovery, we performed development of a supporting technology for drug discovery of antibody drug conjugates by imaging living tumor tissues, while solving problem 1. This technology is expected to lead to an improvement in the success rate of clinical trials. Next, to develop a diagnostic method to predict the response to neoadjuvant chemotherapy with antibody drugs for breast cancer, we performed development of fluorescence imaging of pathological tissues using fluorescent nanoparticles with ultra-high brightness, while solving problem 2. This diagnostic technology makes it possible to evaluate the expression level of the target protein of antibody drug with high quantitative and wide range sensitivity. This improved the accuracy of drug efficacy prediction. Therefore, patients who are expected to have a low drug efficacy will be able to select anticancer drugs with different mechanisms of action. These results of this study showed the reduction of drug discovery costs and improvement of individualized medicine. Thus, this study will greatly contribute to the development of precision medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
February 2021

The advantages and disadvantages of the novel fourth-generation cryoballoon as compared to the second-generation cryoballoon in the current short freeze strategy.

J Interv Card Electrophysiol 2021 Feb 11. Epub 2021 Feb 11.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Shimo-aiduki, Matsuoka, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.

Background: The novel fourth-generation cryoballoon (4-CB) is characterized by a shorter-tip that potentially facilitates better time-to-isolation (TTI) monitoring. We sought to clarify the advantages and disadvantages of the 4-CB compared to the second-generation cryoballoon (2-CB) in pulmonary vein isolation (PVI).

Methods: Forty-one and 49 consecutive atrial fibrillation patients underwent 2-CB and 4th-CB PVIs using 28-mm balloons and short freeze strategies. When effective freezing was not obtained, the CB was switched to the other CB.

Results: The rate of successful PVIs was significantly higher for 2-CBs than 4-CBs (162/162[100%] vs. 178/193[92.2%] PVs, p < 0.0001). The difference was significant for lower PVs, especially right inferior PVs (RIPVs)(p = 0.005). In a total of 15 PVs in 11 patients, 4-CBs were switched to 2-CBs, and 14/15(93.3%) PVs were successfully isolated. The balloon temperature tended to reach -55℃ more frequently with 2-CBs than 4-CBs during RIPV ablations (15/41[36.6%] vs. 12/49[24.5%], p = 0.21). The TTI monitoring capability was significantly higher with 4-CBs than 2-CBs (131/188[69.7%] vs. 83/160[51.9%] PVs, p = 0.0007). The difference was significant for right superior and left inferior PVs, but not for left superior PVs. Even if PVs requiring crossover were excluded, the total freeze duration (715±152 vs. 755±215 seconds, p = 0.31) tended to be shorter for 2-CBs than 4-CBs. The incidence of phrenic nerve injury was similar for 2-CB and 4th-CB ablation (0/41 vs. 2/49, p = 0.12) CONCLUSIONS: The 4-CB's shorter balloon tip enabled a significantly higher capability of TTI monitoring; however, it resulted in significantly lower rates of successful PVIs than the 2-CB, especially for the RIPVs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10840-021-00957-5DOI Listing
February 2021

Discrepancy between CARTO and Rhythmia maps for defining the left atrial low-voltage areas in atrial fibrillation ablation.

Heart Vessels 2021 Jan 28. Epub 2021 Jan 28.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji-cho, yoshida-gun, Fukui, 910-1193, Japan.

Reported mapping procedures of left atrial (LA) low-voltage areas (LVAs) vary widely. This study aimed to compare the PentaRay/CARTO3 (PentaRay map) and Orion™/Rhythmia™ (Orion map) systems for LA voltage mapping. This study included 15 patients who underwent successful pulmonary vein isolation (PVI) for atrial fibrillation. After PVI, PentaRay and Orion maps created for all patients were compared. LVAs were defined as sites with ≥ 3 adjacent low-voltage points < 0.5 mV. LVAs were indicated in 8 (53%) among 15 patients, and the average values of the measured LVAs was comparable between the systems (PentaRay map = 5.4 ± 8.7 cm; Orion map = 4.3 ± 6.4 cm, p = 0.69). However, in 2 of 8 patients with LVAs, the Orion map indicated LVAs at the septum and posterolateral sites of the LA, respectively, whereas the PentaRay map indicated no LVAs. In those patients, sharp electrograms of > 0.5 mV were properly recorded at the septum and posterolateral sites during appropriate beats in the PentaRay map. The PentaRay map had a shorter procedure time than the Orion map (12 ± 3 min vs. 23 ± 8 min, respectively; p < 0.01). Our study results showed a discrepancy in the LVA evaluation between the PentaRay and Orion maps. In 2 of 15 patients, the Orion map indicated LVAs at the sites where > 0.5-mV electrograms were properly recorded in the PentaRay map.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00380-021-01773-7DOI Listing
January 2021

L-type amino acid transporter 1 is associated with chemoresistance in breast cancer via the promotion of amino acid metabolism.

Sci Rep 2021 Jan 12;11(1):589. Epub 2021 Jan 12.

Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.

F-FDG PET/CT has been used as an indicator of chemotherapy effects, but cancer cells can remain even when no FDG uptake is detected, indicating the importance of exploring other metabolomic pathways. Therefore, we explored the amino acid metabolism, including L-type amino acid transporter-1 (LAT1), in breast cancer tissues and clarified the role of LAT1 in therapeutic resistance and clinical outcomes of patients. We evaluated LAT1 expression before and after neoadjuvant chemotherapy and examined the correlation of glucose uptake using FDG-PET with the pathological response of patients. It revealed that LAT1 levels correlated with proliferation after chemotherapy, and amino acid and glucose metabolism were closely correlated. In addition, LAT1 was considered to be involved in treatment resistance and sensitivity only in luminal type breast cancer. Results of in vitro analyses revealed that LAT1 promoted amino acid uptake, which contributed to energy production by supplying amino acids to the TCA cycle. However, in MCF-7 cells treated with chemotherapeutic agents, oncometabolites and branched-chain amino acids also played a pivotal role in energy production and drug resistance, despite decreased glucose metabolism. In conclusion, LAT1 was involved in drug resistance and could be a novel therapeutic target against chemotherapy resistance in luminal type breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-80668-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803739PMC
January 2021

Ultrahigh resolution electroanatomical mapping of the transverse conduction of the right atrial posterior wall in cases with and without typical atrial flutter.

J Cardiovasc Electrophysiol 2021 Feb 29;32(2):297-304. Epub 2020 Dec 29.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.

Introduction: The right atrial posterior wall (RAPW) is known to form a conduction barrier during typical atrial flutter (AFL). We evaluated the transverse conduction properties of RAPW in patients with and without typical AFL using an ultrahigh resolution electroanatomical mapping system.

Methods And Results: This study included 41 patients who underwent catheter ablation of AF, typical or atypical AFL, in whom we performed RAPW mapping with an ultrahigh resolution mapping system during typical AFL and coronary sinus ostial pacing with three different pacing cycle lengths (PCLs) (1) PCL1: PCL within 40 ms of the AFL cycle length in patients with typical AFL or 250-300 ms for those without, (2) PCL2: 400 ms, (3) PCL3: PCL just faster than the sinus rate. Local RAPW conduction block was evaluated by propagation mapping and local double potentials separated by an isoelectric line. The functional block was defined as areas blocked during shorter PCLs but conductive during longer PCLs. The degree of blockade was calculated by dividing the blocked length by RAPW length (%blockade). Only two patients demonstrated a fixed complete RAPW block (100%, %blockade). Thirty-one patients demonstrated a partial block of RAPW, and the %blockade during PCL1-3 was 49.4 ± 19.8%, 39.5 ± 19.2%, and 35.0 ± 22.9% in this group, respectively. Functional block areas were frequently observed above the fixed block area adjacent to the RA-inferior vena cava junction. Transverse conduction block was more frequently observed in patients with typical AFL at any longitudinal level of RAPW.

Conclusion: RAPW transverse conduction block is lower-side dominant and greater in patients with typical AFL than those without.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jce.14850DOI Listing
February 2021

Early repolarization in the inferolateral leads predicts the presence of vasospastic angina: a novel predictor in patients with resting angina.

Coron Artery Dis 2021 Jun;32(4):309-316

Department of Cardiovascular Medicine, University of Fukui, Shimoaizuki, Matsuoka, Eiheiji-cho, Fukui, Japan.

Background: An association between early repolarization and ventricular fibrillation has recently been reported in patients with vasospastic angina (VSA). However, no studies have clarified whether the presence of early repolarization can predict VSA.

Methods: Participants comprised 286 patients (136 males) with clinically suspected VSA who underwent intracoronary provocation tests using acetylcholine or ergonovine. Patients were divided into a VSA group [n = 94, positive provocation test as induction of coronary arterial spasm (>90% stenosis)] and a non-VSA group (n = 192). Detailed early repolarization data were compared between groups.

Results: The VSA group showed a higher frequency of smokers (28.7%) than the non-VSA group (17.2%; P = 0.02). On baseline 12-lead ECG, early repolarization (defined as a J-point elevation ≥0.1 mV from baseline in both or either of inferolateral leads) was found in 39 patients (inferior leads, n = 27; inferolateral leads, n = 12). Early repolarization was found more frequently in the VSA group (28.7%) than in the non-VSA group (6.2%, P < 0.01). Multivariate analysis revealed early repolarization as an independent predictor of VSA (odds ratio, 5.22; 95% confidence interval, 2.41-11.2; P < 0.01). Early repolarization pattern features including inferior lead, higher amplitude, notched type and horizontal/descending ST segments were associated with increased risk of VSA.

Conclusion: In patients with resting chest pain, early repolarization was a predictor of VSA that could be particularly related to the inferior lead, higher amplitude, notched type and horizontal/descending ST segment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MCA.0000000000000983DOI Listing
June 2021

Associations between cachexia and metalloproteinases, haemodynamics and mortality in heart failure.

Eur J Clin Invest 2021 Apr 7;51(4):e13426. Epub 2020 Nov 7.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Eiheiji-cho, Japan.

Background: Addressing cachexia in chronic heart failure (CHF) patients is an urgent issue in Japan, the most aged country in the world. We investigated the possible relationships between cachexia and, metalloproteinases and haemodynamics assessed by the cardiac catheterization. We also clarified the prognostic value of cardiac cachexia in the Japanese CHF population.

Methods And Results: A total of 370 participants (median age, 69 years; 35% women) were included. The haemodynamic effects of cachexia were analysed by right heart catheterization. The serum levels of matrix metalloproteinase (MMP) and tissue inhibitors of MMP (TIMP), as myocardial collagen turnover markers, were also assessed. Cachexia was present in 88 patients (31%). Overall, 59 patients (16%) had all-cause death. Serum MMP-2 and TIMP-2 levels were higher in cachectic patients than in noncachectic patients (797.5 [649.0-1066.8] vs 610.0 [461.8-756.8] ng/mL; P = .004 and 39.0 [28.0-49.0] vs 24.0 [19.0-37.0] ng/mL; P = .008, respectively). Cachectic patients had greater values of pulmonary vascular resistance (PVR) (161.9 [119.4-225.4] vs 127.8 [90.7-164.8] dynes/sec/cm , P = .020). Kaplan-Meier survival analysis demonstrated higher probabilities of all-cause death in the cachexia group (log-rank P = .010). Cox proportional hazards modelling showed cachexia was an independent predictor of mortality (hazard ratio, 1.89; 95% confidence interval, 1.06-3.37; P = .029). The random forest model showed that C-reactive protein, age, haemoglobin, PVR and MMP-2 were predictors of cardiac cachexia.

Conclusions: Cachexia, applying the globally accepted definition, was associated with adverse outcomes in the Japanese CHF population and accompanied by increased activity of MMP species and PVR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/eci.13426DOI Listing
April 2021

Ultra-high resolution mapping and ablation of accessory pathway conduction.

J Interv Card Electrophysiol 2020 Oct 24. Epub 2020 Oct 24.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Shimo-aiduki, Matsuoka, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.

Background: Detailed mapping studies of accessory pathway (AP) conduction have not been previously performed using ultra-high resolution mapping systems. We sought to evaluate the clinical utility of ultra-high resolution mapping systems and the novel "Lumipoint" algorithm in AP ablation.

Methods: This study included 17 patients who underwent AP mapping using minielectrode basket catheters and Rhythmia systems. Ablation was performed with 4-mm irrigated-tip catheters.

Results: Antegrade and retrograde AP conduction was observed in 6 and 16 patients. Atrial activation map was obtained during orthodromic tachycardia and ventricular pacing in 13 (76.5%) and 14 (82.3%) patients, and the earliest activation area was identical. Ventricular activation maps were created during atrial pacing in 3 patients. All maps showed focal activation patterns on global activation histograms, and the valley on the histogram highlighted the earliest activation area. "Complex activation" features further highlighted limited areas with continuous electrical activity during the time period in the majority. APs were located at the mitral and tricuspid annuli in 15 and 2 patients, and all were successfully eliminated with 3.4 ± 0.6 s applications. No patients had recurrences during a median follow-up of 15 [10.5-22.5] months. At successful ablation sites, the local atrial and ventricular electrogram amplitudes and ratio tended to be greater, and fusion or continuous electrical activity between the atrial and ventricular components was more frequently observed on the minielectrode than ablation catheter (17/17 vs. 12/17, p = 0.005).

Conclusions: Ultra-high resolution activation mapping and a novel algorithm facilitated the AP localization. The local electrogram characteristics differed between the minielectrode and ablation catheters.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10840-020-00900-0DOI Listing
October 2020

A case of outflow tract premature ventricular contractions with very distant exit sites suspected to have a single origin.

J Electrocardiol 2020 Nov - Dec;63:41-45. Epub 2020 Oct 8.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.

Outflow tract premature ventricular contractions sometimes demonstrate multiple exit sites in the right and left outflow tracts with preferential pathways. Here we present a case of outflow tract premature ventricular contractions, which were eliminated by ablation from the right ventricular outflow tract accompanied by additional ablation from the very distant endocardial left ventricular outflow tract. The findings during the ablation indicated there was a single origin with multiple exit sites rather than multiple origins for each QRS morphology. This case illustrates that the preferential pathways can demonstrate very distant multiple exit sites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jelectrocard.2020.09.015DOI Listing
October 2020

Mapping and ablation of clinical spontaneous perimitral atrial tachycardias using an ultra-high-resolution mapping system.

Heart Rhythm 2021 Feb 30;18(2):189-198. Epub 2020 Sep 30.

Department of Cardiovascular Medicine, University of Fukui, Fukui, Japan.

Background: Perimitral atrial tachycardias (PMATs) are common atrial tachycardias (ATs), yet their mechanisms vary.

Objective: The purpose of this study was to characterize clinical spontaneous PMATs using an ultra-high-resolution (UHR) mapping system.

Methods: The study included 32 consecutive PMATs in 31 patients who had undergone AT mapping/ablation using a UHR mapping system.

Results: Six, 10, 11, and 5 PMATs occurred in cardiac intervention-naïve (group A), post-lateral/posterior mitral isthmus linear ablation (group B), post-atrial fibrillation ablation without mitral isthmus linear ablation (group C), and post-cardiac surgery (group D) patients, respectively. Group A patients tended to be older, more likely were female, and had sinus node or atrioventricular conduction disturbances more frequently. A 12-lead synchronous isoelectric interval was observed in 15 PMATs (46.9%). Coronary sinus activation was proximal to distal or distal to proximal except in 3 PMATs with straight patterns due to epicardial gaps. Left atrial anterior/septal wall (LAASW) low-voltage areas were smallest in group B. Slow conduction areas (SCAs) were identified in 26 PMATs (81.2%) and were located on the LAASW in all group A and group D patients. Conduction velocity in the SCAs was slowest in group B. In group B, all PMATs were terminated by single applications, and the gaps were located epicardially in 5 of 10 (50%). Anterior (n = 23) or lateral/posterior (n = 9) mitral isthmus linear block was successfully created without any complications in all. Twenty-five concomitant ATs among 18 patients (58.1%) also were eliminated. During a median of 20.0 (11.0-40.0) months of follow-up, 28 patients (90.3%) were free from any atrial tachyarrhythmias.

Conclusion: An UHR mapping-guided approach with identification of the individual tachycardia mechanism should be the preferred strategy given the distinct and complex arrhythmia mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hrthm.2020.09.016DOI Listing
February 2021

Effects of PCSK9 Inhibitor on Favorable Limb Outcomes in Patients with Chronic Limb-Threatening Ischemia.

J Atheroscler Thromb 2020 Sep 25. Epub 2020 Sep 25.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui.

Aim: The aim of this study was to examine the effects of evolocumab on favorable limb events in patients with chronic limb-threatening ischemia (CLTI).

Methods: A single-center, prospective observational study was performed on 30 patients with CLTI. The subjects were divided into 2 groups based on evolocumab administration: evolocumab-treated (E) group (n=14) and evolocumab non-treated (non-E) group (n=16). The primary outcome was 12-month freedom from major amputation. The secondary outcomes were 12-month amputation-free survival (AFS), overall survival (OS), and wound-free limb salvage. The mean follow-up period was 18±11 months.

Results: No significant difference was detected between the two groups for the 12-month freedom from major amputation (log-rank p=0.15), while the 12-month AFS rate was significantly higher in the E group than that in the non-E group (log-rank p=0.02). The 12-month OS rate in the E group was shown a tendency for improvement, as compared with that in the non-E group (log-rank p=0.056). Evolocumab administration was not associated with a significant change in freedom from major amputation (HR, 0.23, 95% CI, 0.03-2.07, p=0.19). However, evolocumab administration was related to a tendency for improvement of AFS and OS (HR, 0.13, 95% CI, 0.02-1.06, p=0.056; HR, 0.16, 95% CI, 0.02-1.37, p=0.09, respectively). Moreover, The E group had a higher proportion of wound-free limb salvage at 12 months (92% vs. 42%, p=0.03).

Conclusion: Evolocumab administration was associated with a better AFS outcome in patients with CLTI. Long-term administration of evolocumab over 12 months contributed to improving proportion of wound-free limb salvage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5551/jat.57653DOI Listing
September 2020

Clinically Manifesting Air Embolisms in Cryoballoon Ablation: Can Novel Water Buckets Reduce the Risk?

JACC Clin Electrophysiol 2020 09;6(9):1067-1072

Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.

Air embolisms can lead to lethal results; however, few reports have systemically investigated this issue. Of 348 consecutive patients with atrial fibrillation who underwent cryoballoon ablation, procedures were performed conventionally in 251 patients. In the remaining 97 patients, a water bucket was used while inserting the cryoballoon into the sheath. A total of 10 coronary air embolisms with ST-segment elevation in the inferior leads were observed among 9 (2.6%) patients. Multiple air bubbles were identified in 2 patients on emergent coronary angiography. All recovered under conservative treatment without any sequela. The incidence decreased when using the water bucket (1 of 97 [1.03%] vs. 8 of 251 [3.2%], p = 0.454).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacep.2020.07.012DOI Listing
September 2020

Placebo-Controlled, Double-Blind Study of Empagliflozin (EMPA) and Implantable Cardioverter-Defibrillator (EMPA-ICD) in Patients with Type 2 Diabetes (T2DM): Rationale and Design.

Diabetes Ther 2020 Nov 23;11(11):2739-2755. Epub 2020 Sep 23.

Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Introduction: Type 2 diabetes (T2DM) is associated with cardiovascular death, including sudden cardiac death due to arrhythmias. Patients with an implantable cardioverter-defibrillator (ICD) are also at high risk of developing a clinically significant ventricular arrhythmia. It has been reported that sodium-glucose cotransporter 2 (SGLT2) inhibitors can reduce cardiovascular deaths; however, the physiological mechanisms of this remain unclear. It is, however, well known that SGLT2 inhibitors increase blood ketone bodies, which have been suggested to have sympatho-suppressive effects. Empagliflozin (EMPA) is an SGLT2 inhibitor. The current clinical trial titled "Placebo-controlled, double-blind study of empagliflozin (EMPA) and implantable cardioverter-defibrillator (EMPA-ICD) in patients with type 2 diabetes (T2DM)" was designed to investigate the antiarrhythmic effects of EMPA.

Methods: The EMPA-ICD study is a prospective, multicenter, placebo-controlled, double-blind, randomized, investigator-initiated clinical trial currently in progress. A total of 210 patients with T2DM (hemoglobin A1c 6.5-10.0%) will be randomized (1:1) to receive once-daily placebo or EMPA, 10 mg, for 24 weeks. The primary endpoint is the number of clinically significant ventricular arrhythmias for 24 weeks before and 24 weeks after study drug administration, as documented by the ICD. The secondary endpoints of the study are the change from baseline concentrations in blood ketone and catecholamine 24 weeks after drug treatment.

Conclusion: The EMPA-ICD study is the first clinical trial to assess the effect of an SGLT2 inhibitor on clinically significant ventricular arrhythmias in patients with T2DM and an ICD.

Trial Registration: Unique trial number, jRCTs031180120 ( https://jrct.niph.go.jp/latest-detail/jRCTs031180120 ).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13300-020-00924-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547938PMC
November 2020

Phrenic nerve stimulation during right ventricular outflow tract pacing: A rare but possible complication.

J Cardiovasc Electrophysiol 2020 12 29;31(12):3330-3333. Epub 2020 Sep 29.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.

Phrenic nerve stimulation (PNS) caused by a right ventricular (RV) lead is an uncommon complication of pacemaker implantations. We demonstrated a case of left PNS caused by an RV lead placed in the RV outflow tract (RVOT). The PNS was dependent on ventricular capture. This case highlighted a risk of PNS even during RVOT pacing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jce.14760DOI Listing
December 2020

Idiopathic right ventricular arrhythmias requiring additional ablation from the left-sided outflow tract: ECG characteristics and efficacy of an anatomical approach.

J Cardiovasc Electrophysiol 2020 10 16;31(10):2653-2664. Epub 2020 Jul 16.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Yoshida-gun, Fukui, Japan.

Introduction: Despite the characteristic electrocardiogram (ECG) findings of early activation during ventricular tachyarrhythmias (VAs) and/or excellent pacemapping in the right ventricular outflow tract (RVOT), some VAs may require additional, left-sided ablation for a cure.

Methods And Results: This study included five patients with idiopathic VAs whose QRS morphologies were highly suggestive of an RVOT origin. The ECG characteristics and intracardiac electrocardiograms during catheter ablation were assessed. In all patients, the clinical VAs had an LBBB QRS morphology and inferior axis with a precordial R/S transition through leads V3-V5, and negative components in lead I. The earliest activation during the VAs (local electrogram-QRS interval = -34 ± 6.8 ms) and excellent pacemapping were obtained at the posterior portion of the RVOT just beneath the pulmonary valve. However, ablation at those sites failed, and the QRS morphology of the VAs changed. During left-sided OT mapping, the earliest activation was found at sites just contralateral to the initially ablated sites of the RVOT (junction of the left and right coronary cusps = 2, left coronary cusp = 3). In spite of the late activation time and poor pacemapping scores, catheter ablation at those sites cured the VAs. Those successful sites were also near the transitional zone from the great cardiac vein to the anterior interventricular vein (GCV-AIV).

Conclusions: Some VAs, highly suggestive of having RVOT origins, require catheter ablation in the left-sided OT near the initially ablated RVOT site. Those VAs have the same ECG characteristics and might have intramural origins in the superobasal LV surrounded by the RVOT, LVOT, and GCV-AIV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jce.14658DOI Listing
October 2020

A multicenter study comparing the outcome of catheter ablation of atrial fibrillation between cryoballoon and radiofrequency ablation in patients with heart failure (CRABL-HF): Study design.

J Arrhythm 2020 Jun 15;36(3):449-455. Epub 2020 Mar 15.

Department of Cardiovascular Medicine National Cerebral and Cardiovascular Center Suita Japan.

Background: Catheter ablation of atrial fibrillation (AF) is increasingly performed worldwide in patients with heart failure (HF). However, it has been recently emphasized that AF ablation in patients with HF is associated with increased risks of procedure-related complications and mortality. There are little data about the differences in the efficacy and safety between cryoballoon (CB) and radiofrequency (RF) ablation of AF in patients with HF.

Methods: The CRABL-HF study is designed as a prospective, multicenter, open-label, controlled, and randomized clinical trial comparing the efficacy and safety of AF ablation between CB and RF ablation in patients with HF (LVEF ≤40%) (UMIN Clinical Trials Registry UMIN000032433). The CRABL-HF study will consist of 110 patients at multicenter in Japan. The patients will be registered and randomly assigned to either the CB ablation or RF ablation group with a 1:1 allocation. The primary endpoint of this study is the occurrence of atrial tachyarrhythmias (ATs) at 1 year with a blanking period of 90 days after ablation. Key secondary endpoints are the success rate of the pulmonary vein isolation, total procedural time, left atrial dwelling time, total fluoroscopy time, radiation exposure, complication rate, composite of all-cause mortality or HF hospitalizations, cardiovascular events, change in left ventricular ejection fraction, and change in quality of life.

Results: The results of this study are currently under investigation.

Conclusion: The CRABL-HF study is being conducted to compare the efficacy and safety of catheter ablation of AF between CB and RF ablation in patients with HF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/joa3.12322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279987PMC
June 2020

Evaluation of an Integrated Device Diagnostics Algorithm to Risk Stratify Heart Failure Patients - Results From the SCAN-HF Study.

Circ J 2020 06 23;84(7):1118-1123. Epub 2020 May 23.

Medtronic Inc.

Background: Integrated device diagnostics, Triage-HF, is useful in risk stratifying patients with heart failure (HF), but its performance for Japanese patients remains unknown. This is a prospective study of Japanese patients treated with a cardiac resynchronization therapy defibrillator (CRT-D), with a Medtronic OptiVol 2.0 feature.Methods and Results:A total of 320 CRT-D patients were enrolled from 2013 to 2017. All received HF treatment in the prior 12 months. Following enrollment, they were followed every 6 months for 48 months (mean, 22 months). Triage-HF-stratified patients at low, medium and high risk statuses at every 30-day period, and HF-related hospitalization occurring for the subsequent 30 days, were evaluated and repeated. The primary endpoint was to assess Triage-HF performance in predicting HF-related hospitalization risk. All device data were available for 279 of 320 patients (NYHA class II or III in 93%; mean left ventricular ejection fraction, 31%). During a total of 5,977 patient-month follow-ups, 89 HF-related hospitalization occurred in 72 patients. The unadjusted event numbers for Low, Medium and High statuses were 19 (0.7%), 42 (1.6%) and 28 (4.1%), respectively. Relative risk of Medium to Low status was 2.18 (95% CI 1.23-3.85) and 5.78 (95% CI 3.34-10.01) for High to Low status. Common contributing factors among the diagnostics included low activity, OptiVol threshold crossing, and elevated night heart rate.

Conclusions: Triage-HF effectively stratified Japanese patients at risk of HF-related hospitalization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1253/circj.CJ-19-1143DOI Listing
June 2020

Heterogeneous Drug Efficacy of an Antibody-Drug Conjugate Visualized Using Simultaneous Imaging of Its Delivery and Intracellular Damage in Living Tumor Tissues.

Transl Oncol 2020 Jun 11;13(6):100764. Epub 2020 May 11.

Department of Breast and Endocrine Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.

Anticancer drug efficacy varies because the delivery of drugs within tumors and tumor responses are heterogeneous; however, these features are often more homogenous in vitro. This difference makes it difficult to accurately determine drug efficacy. Therefore, it is important to use living tumor tissues in preclinical trials to observe the heterogeneity in drug distribution and cell characteristics in tumors. In the present study, to accurately evaluate the efficacy of an antibody-drug conjugate (ADC) containing a microtubule inhibitor, we established a cell line that expresses a fusion of end-binding protein 1 and enhanced green fluorescent protein that serves as a microtubule plus-end-tracking protein allowing the visualization of microtubule dynamics. This cell line was xenografted into mice to create a model of living tumor tissue. The tumor cells possessed a greater number of microtubules with plus-ends, a greater number of meandering microtubules, and a slower rate of microtubule polymerization than the in vitro cells. In tumor tissues treated with fluorescent dye-labeled ADCs, heterogeneity was observed in the delivery of the drug to tumor cells, and microtubule dynamics were inhibited in a concentration-dependent manner. Moreover, a difference in drug sensitivity was observed between in vitro cells and tumor cells; compared with in vitro cells, tumor cells were more sensitive to changes in the concentration of the ADC. This study is the first to simultaneously evaluate the delivery and intracellular efficacy of ADCs in living tumor tissue. Accurate evaluation of the efficacy of ADCs is important for the development of effective anticancer drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tranon.2020.100764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218300PMC
June 2020

Trastuzumab, pertuzumab, and eribulin mesylate versus trastuzumab, pertuzumab, and a taxane as a first-line or second-line treatment for HER2-positive, locally advanced or metastatic breast cancer: study protocol for a randomized controlled, non-inferiority, phase III trial in Japan (JBCRG-M06/EMERALD).

Trials 2020 May 7;21(1):391. Epub 2020 May 7.

Breast Oncology Center, The Cancer Institute Hospital of JFCR, 3-8-31 Ariake Koto-ku, Tokyo, 135-8550, Japan.

Background: Trastuzumab (Tmab), pertuzumab (Pmab), and taxane has been a standard first-line treatment for recurrent or metastatic human epidermal growth factor (HER2)-positive breast cancer (HER2 mBC) but has some safety issues due to taxane-induced toxicities. This has led to ongoing efforts to seek less toxic alternatives to taxanes that are equally effective when used in combination with Tmab plus Pmab. This study aims to show the non-inferiority of eribulin, a non-taxane microtubule inhibitor, against taxane, as a partner for dual HER2 blockade.

Methods/design: This multicenter, randomized, open-label, parallel-group, phase III study will involve a total of 480 Japanese women with HER2 mBC who meet the following requirements: (1) age 20-70 years; (2) no prior cytotoxic chemotherapy (excluding trastuzumab-emtansine) for mBC; (3) ≥ 6 months after prior neoadjuvant or adjuvant cytotoxic chemotherapy; (4) presence of any radiologically evaluable lesion; (5) left ventricular ejection fraction ≥ 50%; (6) Eastern Cooperative Oncology Group performance status score of 0 or 1; (7) adequate organ function; and (8) life expectancy of at least 6 months. They will be randomized 1:1 to receive eribulin (1.4 mg/m on days 1 and 8) or taxane (docetaxel 75 mg/m on day 1 or paclitaxel 80 mg/m on days 1, 8, and 15) in combination with Tmab (8 mg/kg then 6 mg/kg) plus Pmab (840 mg then 420 mg) on day 1 of each 21-day cycle. The treatment will be continued until disease progression or unmanageable toxicity. The primary endpoint is progression-free survival as per investigator according to RECIST v1.1 criteria. Key secondary endpoints include objective response rate, overall survival, quality of life and safety. Non-inferiority will be tested with two margins of 1.33 and 1.25 in a stepwise manner. If non-inferiority is shown with a margin of 1.25, superiority will then be tested.

Discussion: If this study shows the non-inferiority, or even superiority, of Tmab, Pmab, and eribulin against the existing taxane-containing regimen, this new regimen may become a standard first- or second-line treatment option for HER2 mBC in Japan.

Trial Registration: ClinicalTrials.gov, ID: NCT03264547. Registered on 28 June 2017.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-020-04341-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206765PMC
May 2020