Search

Background: GDF15 plays pivotal metabolic roles in nutritional stress and serves as a physiological regulator of energy balance. However, the patterns of GDF15 levels in underweight or obese patients with chronic heart failure (CHF) are not well-understood., Methods: We assessed serum GDF15 levels at baseline and 3 years and the temporal changes in 940 Japanese patients (642 paired samples), as a sub-analysis of the SUPPORT trial (age 65.9 ± 10.1 years). The GDF15 levels were analyzed across BMI groups (underweight [<18.5 kg/m 2 ; n = 50], healthy weight [18.5-22.9; n = 27 5], overweight [23-24.9; n = 234], and obese [≥25; n = 381]), following WHO recommendations for the Asian-Pacific population. Landmark analysis at 3 years assessed the association between GDF15 levels and HF hospitalization or all-cause death., Results: Compared to the healthy weight group, the underweight group included more females (54.0%) with advanced HF (NYHA class III; 20.0%) and exhibited increased GDF15 level (1764 pg/mL [IQR 1067-2633]). Obese patients, younger (64.2 years) and diabetic (53%), had a similar GDF15 level to the healthy weight group. A higher baseline GDF15 level was associated with worse outcomes across the BMI spectrum. GDF15 increased by 208 [21-596] pg/mL over 3 years, with the most substantial increase observed in the underweight group (by +28.9% [6.2-81.0]). Persistently high GDF15 levels (≥1800 pg/mL) was independently associated with worse outcomes after 3 years (adjusted HR 1.8 [95%CI 1.1-2.9])., Conclusions: In underweight patients with CHF, GDF15 level was elevated at baseline and experienced the most significant increase over 3 years. Its consistent elevation suggested a worse outcome., Competing Interests: Declaration of competing interest H.S. has received lecture fees from Bayer Yakuhin, Ltd. (Osaka, Japan) and Daiichi Sankyo Co., Ltd. (Tokyo, Japan). ETK received lecture fees from Bayer Yakuhin, Ltd. outside of the current work. The remaining authors have nothing to disclose., (Copyright © 2023. Published by Elsevier B.V.)

Background: Various cardiovascular diseases cause acquired von Willebrand syndrome (AVWS), which is characterized by a decrease in high-molecular-weight (large) von Willebrand factor (VWF) multimers. Mitral regurgitation (MR) has been reported as a cause of AVWS. However, much remains unclear about AVWS associated with MR., Objectives: To evaluate VWF multimers in MR patients and examine their impact on clinical characteristics., Methods: Moderate or severe MR patients ( n  = 84) were enrolled. VWF parameters such as the VWF large multimer index (VWF-LMI), a quantitative value that represents the amount of VWF large multimers, and clinical data were prospectively analyzed., Results: At baseline, the mean hemoglobin level was 12.9 ± 1.9 g/dL and 58 patients (69.0%) showed loss of VWF large multimers defined as VWF-LMI < 80%. VWF-LMI in patients with degenerative MR was lower than in those with functional MR. VWF-LMI appeared to be restored the day after mitral valve intervention, and the improvement was maintained 1 month after the intervention. Seven patients (8.3%) had a history of bleeding, 6 (7.1%) of whom had gastrointestinal bleeding. Gastrointestinal endoscopy was performed in 23 patients (27.4%) to investigate overt gastrointestinal bleeding, anemia, etc. Angiodysplasia was detected in 2 of the 23 patients (8.7%)., Conclusion: Moderate or severe MR is frequently associated with loss of VWF large multimers, and degenerative MR may cause more severe loss compared with functional MR. Mitral valve intervention corrects the loss of VWF large multimers. Gastrointestinal bleeding may be relatively less frequent and hemoglobin level remains stable in MR patients., (© 2024 The Authors.)

Background: Severe aortic stenosis (AS) causes acquired von Willebrand syndrome by the excessive shear stress-dependent cleavage of high molecular weight multimers of von Willebrand factor (VWF). While the current standard diagnostic method is so-called VWF multimer analysis that is western blotting under nonreducing conditions, it remains unclear whether a ratio of VWF Ristocetin co-factor activity (VWF:RCo) to VWF antigen levels (VWF:Ag) of <0.7, which can be measured with an automated coagulation analyzer in clinical laboratories and is used for the diagnosis of hereditary von Willebrand disease., Objectives: To evaluated whether the VWF:RCo/VWF:Ag is useful for the diagnosis of AS-induced acquired von Willebrand syndrome., Methods: VWF:RCo and VWF:Ag were evaluated with the VWF large multimer index as a reference, which represents the percentage of a patient's VWF high molecular weight multimer ratio to that of standard plasma in the VWF multimer analysis., Results: We analyzed 382 patients with AS having transaortic valve maximal pressure gradients of >30 mmHg, 27 patients with peripheral artery disease, and 46 control patients free of cardiovascular disease with osteoarthritis, diabetes, and so on. We assumed a large multimer index of <80% as loss of VWF large multimers since 59.0% of patients with severe AS had the indices of <80%, while no control patients or patients with peripheral artery disease, except for 2 patients, exhibited the indices of <80%. The VWF:RCo/VWF:Ag ratios, measured using an automated blood coagulation analyzer, were correlated with the indices (r s  = 0.470, P  < .001). When the ratio of <0.7 was used as a cut-off point, the sensitivity and specificity to VWF large multimer indices of <80% were 0.437 and 0.826, respectively., Conclusion: VWF:RCo/VWF:Ag ratios of <0.7 may indicate loss of VWF large multimers with high specificity, but low sensitivity. VWF:RCo/VWF:Ag ratios in patients with AS having a ratio of <0.7 may be useful for monitoring the loss of VWF large multimers during their clinical courses., (© 2023 The Author(s).)

Background: Establishing the appropriate rivaroxaban dose in older patients with non-valvular atrial fibrillation (NVAF) is important because of the high risk of adverse events. In this EXPAND study subanalysis, we examined the safety and efficacy of standard-dose (15 mg/day) and non-recommended reduced-dose (10 mg/day) rivaroxaban in patients aged ≥65 years with NVAF and preserved renal function., Methods: The entire analysis population (ALL cohort [n = 3982]; ≥65 years) was divided into early elderly (ELD) (65-74 years [n = 1444]) and late ELD (≥75 years [n = 2386]) sub-cohorts. Each sub-cohort was divided into reduced-dose and standard-dose groups. Kaplan-Meier survival curves with adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were used to assess efficacy (thromboembolic events) and safety (hemorrhagic events) outcomes., Results: The aHR for major bleeding did not differ between the dosages in any of the cohorts (aHRs: 0.86-0.93). There were no significant differences in the occurrence of stroke + systemic embolism (SE) or stroke + SE + myocardial infarction (MI) + cardiovascular (CV) death among the cohorts. The aHR for MI/unstable angina + interventional/CV surgery + CV death was higher with 10-mg/day rivaroxaban than 15-mg/day rivaroxaban in the ALL cohort (aHR: 1.56 [95% CI 1.02-2.37], p = 0.039) and the late ELD sub-cohort (aHR: 1.86 [95% CI 1.01-3.42], p = 0.045)., Conclusions: Reduced-dose rivaroxaban may increase the risk of coronary artery events. The use of rivaroxaban 15 mg/day in patients with NVAF aged ≥75 years with preserved renal function was supported., Competing Interests: Declaration of Competing Interest All authors have received funding support from Bayer Yakuhin Ltd. throughout the implementation of the EXPAND Study, including reporting of this sub-analysis. Other disclosures are as follows; WS has received honoraria from Daiichi-Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Bayer Yakuhin Ltd., Pfizer Co. Ltd., and Bristol-Myers Squibb K. K.; TU has received consulting fees from LSI Medience, Inc.; HA has received honoraria from Daiichi-Sankyo Co. Ltd.; HI has received honoraria from Daiichi-Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Bayer Yakuhin Ltd., and Bristol-Myers Squibb K. K.; TK has received honoraria from Daiichi-Sankyo Co. Ltd. and Bayer Yakuhin, Ltd., and scholarship from Takeda Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Asahi Kasei Medical Co., Ltd., Shionogi & Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Teijin Pharma, Ltd., Kowa Co. Ltd., Bayer Yakuhin, Ltd., Eisai Co., Ltd., Sumitomo Pharma Co., Ltd., Daiichi-Sankyo Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Torii Pharmaceutical Co., Ltd., AbbVie GK, EA Pharma Co.,Ltd., Kyowa Kirin Co., Ltd., Zeria Pharmceutical Co., Ltd., Eli Lilly Japan K.K., Sanwa Kagaku Kenkyusho Co., Ltd., Mochida Pharmaceutical Co.,Ltd., Ono Pharmaceutical Co., Ltd., and Novo Nordisk Pharma Ltd.; TY has received consulting fees from Daiichi-Sankyo Co. Ltd., Novartis Pharma K. K., and Toa Eiyo Ltd., and honoraria from Daiichi-Sankyo Co., Ltd., Bayer Yakuhin Ltd., and Bristol-Myers Squibb K. K., and Novartis Pharma K. K.; TI has received grants from Daiichi-Sankyo Co. Ltd., and honoraria from Bayer Yakuhin Ltd., Daiichi-Sankyo Co. Ltd., and Pfizer Japan Inc.; MK has received honoraria from Daiichi-Sankyo Co. Ltd. and had board participations on a trial sponsored by Daiichi-Sankyo Co. Ltd.; KK has grants from Bayer Yakuhin Ltd., Daiichi-Sankyo Co. Ltd., Abbott Medical Co. Ltd. and honoraria from Bayer Yakuhin Ltd., Daiichi-Sankyo Co. Ltd., Novartis Pharma AG., and Otsuka Pharmaceutical Co. Ltd., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: This study aimed to examine whether high-sensitivity cardiac troponin-I (hsTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) could predict future major adverse cardiovascular events (MACE) in stable coronary artery disease (CAD) patients with high- or low-dose of pitavastatin., Methods: This was a case-cohort analysis of the REAL-CAD study, a randomized trial of high- or low-dose (4 or 1 mg/day) pitavastatin therapy in patients with stable CAD. We examined the MACE risk according to the quartile of hsTnI and NT-proBNP at baseline., Results: A total of 1336 and 1396 patients including 582 MACE cases were randomly examined into the hsTnI and NT-proBNP cohort, respectively. Both higher levels of hsTnI and NT-proBNP at baseline were significantly associated with increased risk of MACE (p < 0.001, respectively). When separately analyzed in statin dose, the higher marker levels were significantly associated with higher MACE risk in all cohorts (p < 0.001 in all cohorts). After multivariable adjustment, hsTnI levels were significantly associated with MACE risk in low-dose statin group (HR 2.54, p = 0.0001); however, in high-dose pitavastatin therapy, a significant association was diminished in MACE risk among the quartiles of baseline hsTnI levels (p = 0.154). Conversely in the NT-proBNP cohort, the association between NT-proBNP levels and MACE risk was constantly observed regardless of pitavastatin dose even after multivariable adjustment (both p < 0.0001)., Conclusions: Patients with high hsTnI levels had high risk of MACE in low-dose statin group, but not in high-dose, suggesting that high-dose statin treatment might decrease MACE risk in stable CAD patients with high hsTnI levels., Competing Interests: Declaration of Competing Interest Dr. J. Ishii received a research grant from Sysmex Corp. and honoraria from Daiichi Sankyo Co. Ltd., Kowa Pharmaceutical Co. Ltd., Siemens Healthineers Japan, and LSI Medience Corp. Dr. Fukumoto received research grant from Sanofi KK, Shionogi & Co, Ltd., honoraria from Public Health Research Foundation, AstraZeneca KK, Eisai Co, Ltd., Kowa Pharmaceutical Co Ltd., research grant and honoraria from MSD KK, Otsuka Pharmaceutical Co, Ltd., Daiichi Sankyo Co, Ltd., Sumitomo Dainippon Pharma Co, Ltd., Teijin Pharma Ltd., Bayer Yakuhin, Ltd., Mochida Pharmaceutical Co, Ltd., Astellas Pharma Inc., Sanwa Kagaku Kenkyusho Co, Ltd., Takeda Pharmaceutical Co Ltd., Mitsubishi Tanabe Pharma Corp, Pfizer Japan Inc., Ono Pharmaceutical Co Ltd., AstraZeneca KK. Dr. Ozaki received research grant and honoraria from Mochida Pharmaceutical Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Company Limited, Sanofi K.K., Shionogi & Co., Ltd., MSD K.K., Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., research grant, other reserch support and honoraria from Public Health Research Foundation. Dr. Iimuro received research grant from Amgen Astellas BioPharma K.K., research grant and honoraria from Public Health Research Foundation. Dr. Iwata received other research support from Public Health Research Foundation, honoraria from Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Takeda Pharmaceutical Company Limited, MSD K.K., Kowa Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation. Dr. Sakuma received honoraria from GlaxoSmithKline, AstraZeneca, Takeda, Bayer, Pfizer, Bristol-Myers Squibb, Boehringer lngelheim, MSD, Kyowa Hakko Kirin, Daiichi Sankyo, Novartis, Sanofi, Kowa, Shionogi, Kissei, Astellas, Amgen, Ono, Otsuka, Novonordisk, Mochida, Teijin, Sysmex, Nipro, Kyorin, Fuji and Sumitomo Dainippon, research grants from Public Health Research Foundation, Kowa, National Cerebral and Cardiovascular Center and Medical Informatics Study Group. Dr. Nakagawa received honoraria from Kowa Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Bayer Yakuhin, Ltd., Sanofi K.K., Daiichi Sankyo Company, Limited, Shionogi & Co., Ltd., Astellas Pharma Inc., MSD K.K., Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., AstraZeneca K.K., Amgen Astellas BioPharma K.K., Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., research grant, other research support and honoraria from Public Health Research Foundation. Dr. Hibi received research grants from Public Health Research Foundation, Abott Vascular Japan Co. Ltd., and Sanofi KK. Dr. Hiro received research grants from Otsuka Pharmaceutical Co. Ltd., Shionogi & Co. Ltd., and Takeda Pharmaceutical Co. Ltd., honoraria from Amgen Astellas BioPharma KK, Kowa Pharmaceutical Co. Ltd., Kissei Pharmaceutical Co. Ltd., and Chugai Pharmaceutical Co. Ltd., research grants and honoraria from Astellas Pharma Inc., Eisai Co. Ltd., MSD KK, Sanofi KK, Daiichi Sankyo Co. Ltd., Sumitomo Dainippon Pharma Co. Ltd., Mitsubishi Tanabe Pharma Corp., Bayer Yakuhin, Ltd., Pfizer Japan Inc., and AstraZeneca KK, and research grant, other research support, and honoraria from Public Health Research Foundation. Dr. Hokimoto received honoraria from Daiichi Sankyo Co. Ltd. and AstraZeneca KK. Dr. Miyauchi received honoraria from Sanofi KK, Daiichi Sankyo Co. Ltd., AstraZeneca KK, Amgen Astellas BioPharma KK, Takeda Pharmaceutical Co. Ltd., Bayer Yakuhin, Ltd., and MSD KK. Dr. Daida received honoraria from Amgen Astellas BioPharma KK, Daiichi Sankyo Co., Ltd., Kowa Pharmaceutical Co., Ltd., MSD KK, and research grant from Canon, and scholarship grant from Otsuka Pharmaceutical Co., Ltd., Sanofi KK, MSD KK, Pfizer Japan Inc., Mitsubishi Tanabe Pharma Corp., Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Shionogi & Co., Ltd., Actelion Pharmaceuticals Japan, Ltd. Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan Co., Ltd., and courses endowed by Phillips, Resmed, Fukuda Denshi, Asahikasei, Inter-Reha. Dr. Shimokawa received research grant from Shionogi & Co, Ltd., Teijin Pharma Ltd., Astellas Pharma Inc., Otsuka Pharmaceutical Co, Ltd., honoraria from Kowa Pharmaceutical Co Ltd., Sanofi KK, AstraZeneca KK, Bayer Yakuhin, Ltd., research grant and honoraria from MSD KK, Mitsubishi Tanabe Pharma Corp, Daiichi Sankyo Co, Ltd., research grant, other research support, and honoraria from Public Health Research Foundation. Dr. Saito received honoraria from Otsuka Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corp., Mochida Pharmaceutical Co. Ltd., and Kowa Pharmaceutical Co. Ltd. and other research support and honoraria from Public Health Research Foundation. Dr. Kimura received research grant from Sumitomo Dainippon Pharma Co, Ltd., Astellas Pharma Inc., Otsuka Pharmaceutical Co, Ltd., Mitsubishi Tanabe Pharma Corp, Takeda Pharmaceutical Co Ltd., other research support and honoraria from Kowa Pharmaceutical Co Ltd., Bayer Yakuhin, Ltd., research grant, other research support, and honoraria from MSD KK, Sanofi KK, Mochida Pharmaceutical Co, Ltd., Daiichi Sankyo Co, Ltd., Public Health Research Foundation, Amgen Astellas BioPharma KK. Dr. Matsuzaki received honoraria from Mochida Pharmaceutical Co. Ltd. Dr. Nagai received honoraria from Kowa Pharmaceutical Co Ltd., Takeda Pharmaceutical Co Ltd., Bayer Yakuhin, Ltd., Daiichi Sankyo Co, Ltd., Shionogi & Co, Ltd., MSD KK, Mitsubishi Tanabe Pharma Corp, Amgen Astellas BioPharma KK, Eisai Co, Ltd., Astellas Pharma Inc., Sumitomo Dainippon Pharma Co, Ltd., Mochida Pharmaceutical Co, Ltd., honoraria and expert witness from Public Health Research Foundation. Other coauthors report no conflicts., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Prognosis of breast cancer patients has been improved along with the progress in cancer therapies. However, cancer therapeutics-related cardiac dysfunction (CTRCD) has been an emerging issue. For early detection of CTRCD, we examined whether native T1 mapping and global longitudinal strain (GLS) using cardiac magnetic resonance (CMR) and biomarkers analysis are useful., Methods: We prospectively enrolled 83 consecutive chemotherapy-naïve female patients with breast cancer (mean age, 56 ± 13 yrs.) between 2017 and 2020. CTRCD was defined based on echocardiography as left ventricular ejection fraction (LVEF) below 53% at any follow-up period with LVEF>10% points decrease from baseline after chemotherapy. To evaluate cardiac function, CMR (at baseline and 6 months), 12‑lead ECG, echocardiography, and biomarkers (at baseline and every 3 months) were evaluated., Results: A total of 164 CMRs were performed in 83 patients. LVEF and GLS were significantly decreased after chemotherapy (LVEF, from 71.2 ± 4.4 to 67.6 ± 5.8%; GLS, from -27.9 ± 3.9 to -24.7 ± 3.5%, respectively, both P < 0.01). Native T1 value also significantly elevated after chemotherapy (from 1283 ± 36 to 1308 ± 39 msec, P < 0.01). Among the 83 patients, 7 (8.4%) developed CTRCD. Of note, native T1 value before chemotherapy was significantly higher in patients with CTRCD than in those without it (1352 ± 29 vs. 1278 ± 30 msec, P < 0.01). The multivariable logistic regression analysis revealed that native T1 value was an independent predictive factor for the development of CTRCD [OR 2.33; 95%CI 1.15-4.75, P = 0.02]., Conclusions: These results indicate that CMR is useful to detect chemotherapy-related myocardial damage and predict for the development of CTRCD in breast cancer patients., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Statins are generally used for patients with coronary artery disease. However, the impact of statins in patients with vasospastic angina (VSA) is not fully understood., Methods: In a multicenter registry study of the Japanese Coronary Spasm Association (n = 1429), patients with or without statins were compared. The primary endpoint was major adverse cardiac events (MACEs), defined as cardiac death, non-fatal myocardial infarction, unstable angina, heart failure, and appropriate implantable cardioverter defibrillator shock. Propensity score matching and a multivariable Cox proportional hazard model were used to adjust for selection bias in treatment and potential confounding factors., Results: In the whole population, 469 patients received statins, while 960 patients did not receive statins. Patients with statins had a greater prevalence of comorbidities, including hypertension, diabetes, dyslipidemia, and smoking, in comparison to those without statins. The prevalence rates of previous myocardial infarction, significant organic stenosis, and medication use (including calcium channel blockers, angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, and beta blockers) were greater in patients with statins than in those without statins. After propensity matching (n = 211 for both groups), a Kaplan-Meier curve analysis revealed that the incidence of MACE was comparable between patients with and without statins (p = 0.686). MACEs occurred in 6.0% of patients with statins and in 5.9% of those without statins (p = 0.98)., Conclusion: In this multicenter registry study, statin therapy did not reduce clinical events in VSA patients., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Although population studies have implicated emotional burden in asthma severity, the underlying genetic risk factors are not completely understood. We aimed to evaluate the genetic influence of a functional single-nucleotide polymorphism (SNP) in the stress-related μ-opioid receptor gene (OPRM1; A118G SNP, rs1799971) on asthma severity., Methods: We initially assessed disease severity in asthmatic outpatients carrying A118G. Using an ovalbumin-induced experimental asthma rodent model harboring the functionally equivalent SNP, we investigated the mechanism by which this SNP influences the allergic immune response., Results: Among 292 outpatients, 168 underwent airway hyperresponsiveness (AHR) to methacholine testing. Compared with patients carrying the AA and AG genotypes, those carrying the GG genotype exhibited enhanced AHR. The stress levels were presumed to be moderate among patients and were comparable among genotypes. Compared with Oprm1 AA mice, GG mice demonstrated aggravated asthma-related features and increased pulmonary interleukin-4 + CD4 + effector and effector memory T cells under everyday life stress conditions. Intraperitoneal naloxone methiodide injection reduced effector CD4 + T cell elevation associated with increased eosinophil numbers in bronchoalveolar lavage fluid of GG mice to the levels in AA mice, suggesting that elevated Th2 cell generation in the bronchial lymph node (BLN) of GG mice induces enhanced eosinophilic inflammation., Conclusions: Without forced stress exposure, patients with asthma carrying the OPRM1 GG genotype exhibit enhanced AHR, attributable to enhanced Th2 cell differentiation in the regional lymph node. Further research is necessary to elucidate the role of the OPRM1 A118G genotype in the Th2 cell differentiation pathway in the BLN., (Copyright © 2021 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Introduction: Takotsubo syndrome (TTS) is triggered mostly by physical and/or emotional stress that is processed in stress-associated brain regions, including the amygdala. However, it remains unclear whether such stress-induced brain activity is associated with TTS onset., Methods and Results: We acquired brain [ 18 F]-2-fluoro-deoxy-d-glucose ( 18 F-FDG) positron emission tomography in 4 TTS patients (44-82 yrs., 3 women) on days 2-4 (acute phase) and days 29-40 (recovery phase) after diagnosis of TTS was made by coronary angiography and left ventriculogram. The 18 F-FDG uptake was measured globally and also in the pre-defined regions of interest of the bilateral amygdala on the common Montreal Neurological Institute space; all 18 F-FDG images were normalized using automated image pre-processing. Amygdalar activity was calculated by dividing the 18 F-FDG uptake of the amygdala by the global brain uptake. Left ventriculograms showed that apical ballooning was typical at diagnosis and was then relieved in the recovery phase. Amygdalar activity in the acute phase (0.872 ± 0.032) was higher than in the recovery phase (0.805 ± 0.037) (P = 0.013)., Conclusions: We report here 4 cases of TTS showing higher amygdalar activity in the acute phase as compared with the recovery phase, suggesting that increased stress-induced neurobiological activity is associated with TTS onset., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: In vasospastic angina (VSA), coronary vasomotion abnormalities could develop not only in epicardial coronary arteries but also in coronary microvessels, where calcium channel blockers (CCBs) have limited efficacy. However, efficacy of exercise training for VSA remains to be elucidated. We thus aimed to examine whether vasodilator capacity of coronary microvessels is impaired in VSA patients, and if so, whether exercise exerts beneficial effects on the top of CCBs., Methods: We performed 2 clinical protocols. In the protocol 1, we measured myocardial blood flow (MBF) using adenosine-stress dynamic computed tomography perfusion (CTP) in 38 consecutive VSA patients and 17 non-VSA controls. In the protocol 2, we conducted randomized controlled trial, where 20 VSA patients were randomly assigned to either 3-month exercise training group (Exercise group) or Non-Exercise group (n= 10 each)., Results: In the protocol 1, MBF on CTP was significantly decreased in the VSA group compared with the Non-VSA group (138 ± 6 vs 166 ± 10 ml/100 g/min, P = 0.02). In the protocol 2, exercise capacity was significantly increased in the Exercise group than in the Non-Exercise group (11.5 ± 0.5 to 15.4 ± 1.8 vs 12.6 ± 0.7 to 14.0 ± 0.8 ml/min/kg, P < 0.01). MBF was also significantly improved after 3 months only in the Exercise group (Exercise group, 145 ± 12 to 172 ± 8 ml/100 g/min, P < 0.04; Non-Exercise group, 143 ± 14 to 167 ± 8 ml/100 g/min, P = 0.11), although there were no significant between-group differences., Conclusions: These results provide the first evidence that, in VSA patients, exercise training on the top of CCBs treatment may be useful to improve physical performance, although its effect on MBF may be minimal., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier B.V.)

Objectives: Whether there are prognostic links between coronary morphologies and coronary functional abnormalities was examined in ischemia and nonobstructive coronary artery disease (INOCA) patients., Background: Although INOCA has attracted much attention, little is known about the prognostic impact of coronary morphologies in this disorder., Methods: A total of 329 consecutive INOCA patients were enrolled and underwent spasm provocation testing combined with lactate sampling for diagnosis of epicardial and microvascular spasm (MVS). On the basis of the functional tests, the patients were classified into 4 groups: a control group without epicardial spasm or MVS (n = 32), MVS alone (n = 51), diffuse spasm in ≥2 coronary segments (n = 204), and focal spasm in 1 segment (n = 42). In this population, optical coherence tomography imaging of the left anterior descending coronary artery was performed for evaluation of adventitial vasa vasorum (AVV) and intraplaque neovessels (IPN). Index of microcirculatory resistance was also measured., Results: MVS frequently coexisted with diffuse (70%) and focal spasm (68%) with a good correlation between AVV and index of microcirculatory resistance (R = 0.353; p = 0.022). For a median follow-up of 1,043 days, focal spasm showed the worst prognosis (log rank p = 0.005), for which IPN was a significant prognostic factor. By contrast, diffuse spasm showed the greatest AVV with an intermediate prognosis. The prognostic value of INOCA was significantly enhanced by adding AVV and IPN to the physiological indices (area under the curve = 0.88 vs. 0.76; p = 0.048)., Conclusions: These results provide the first evidence that there are important prognostic links between coronary morphologies (evaluated by optical coherence tomography) and coronary functional abnormalities in patients with INOCA, indicating the importance of both evaluations in this population., Competing Interests: Funding Support and Author Disclosures This work was supported in part by grants-in-aid (to Dr. Nishimiya) for Scientific Research (19K17511). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Ischemic heart disease secondary to coronary vascular dysfunction causes angina and impairs quality of life and prognosis. About one-half of patients with symptoms and signs of ischemia turn out not to have obstructive coronary artery disease, and coronary vascular dysfunction may be relevant. Adjunctive tests of coronary vasomotion include guidewire-based techniques with adenosine and reactivity testing, typically by intracoronary infusion of acetylcholine. The CorMicA (Coronary Microvascular Angina) trial provided evidence that routine management guided by an interventional diagnostic procedure and stratified therapy improves angina and quality of life in patients with angina but no obstructive coronary artery disease. In this paper, the COVADIS study group provide a comprehensive review of why, how, and when coronary vascular dysfunction should be assessed invasively. They discuss the rationale through a shared understanding of vascular pathophysiology and clinical evidence. They propose a consensus approach to how an interventional diagnostic procedure is performed with focus on practical aspects. Finally, the authors discuss the clinical scenarios in patients with stable and acute coronary syndromes in which measurement of coronary vascular function may be helpful for patient care., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although depressive symptoms increased mortality and hospitalization in chronic heart failure (CHF) patients, the underlying mechanism remains unclear. The aim of this study was to investigate whether an alteration in hippocampal perfusion, which is the neural substrate of depressive symptoms, is associated with changes in cardiac structures and/or functions in CHF patients., Methods: We used baseline data of 70 CHF patients (66.8 ± 8.9 yrs, 32.5% women), including cerebral blood flow (CBF) in the hippocampus, geriatric depression scale (GDS) scores and echocardiographic parameters, in the Brain Assessment and Investigation in Heart Failure Trial (B-HeFT) (UMIN000008584). Echocardiography was repeated at 3.1 ± 0.5 years after the baseline evaluation. We first tested voxel-wise regression model with hippocampal CBF as dependent variable and each of echocardiographic parameter change as independent variable, adjusted for age and sex. Structural equation modeling was used to test a mediation effect of cognitive test scores on associations between hippocampal perfusion and changes in cardiac structures and/or functions., Results: Baseline anterior hippocampal CBF was negatively correlated with changes in left ventricular posterior wall thickness (PWT) (P < 0.05 with family-wise error corrections). An existence of depressive symptoms was positively correlated with the baseline anterior CBF and negatively with the PWT changes (P < 0.05, both). There were both direct effects of the baseline anterior hippocampal CBF on PWT thinning and effects mediated through the depressive symptoms (P < 0.05, both)., Conclusions: This study provides the first evidence that the alteration in hippocampal perfusion may lead to changes in cardiac structures via increase in depressive symptoms in CHF patients., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: Asymptomatic patients with structural heart diseases are classified as a population at high risk for heart failure (HF) in Stage B. However, limited data are available regarding incidence and related factors of de-novo HF (DNHF) considering competing risk in this population., Methods and Results: In 3362 Stage B patients (mean age 68 yrs, male 76%) from the CHART-2 Study (N = 10,219), we examined incidence of death and DNHF, defined as the first episode of either HF hospitalization or HF death, and factors related to DNHF., Results: During the median 6.0-year follow-up, 627 deaths (31/1000 person-years) and 293 DNHF (15/1000 person-years) occurred. Among the 627 deaths, 212 (34%) and 325 (52%) were specified as cardiovascular and non-cardiovascular deaths, respectively. During the follow-up of 271 DNHF hospitalizations, we observed 124 deaths, including 65 (52%) cardiovascular and 47 (40%) non-cardiovascular deaths. The competing risk model showed that age, diabetes mellitus, stroke, atrial fibrillation, diastolic blood pressure, hemoglobin levels, estimated glomerular filtration ratio and left ventricular ejection fraction was significantly associated with DNHF. Bayesian structural equation modeling showed that many of these cardiac and non-cardiac variables contribute to DNHF by affecting each other, while diabetes mellitus was independently associated with DNHF., Conclusions: Stage B patients had a high incidence of DNHF as well as that of death due to both cardiovascular and non-cardiovascular causes. Thus, management of Stage B patients should include multidisciplinary approaches considering both cardiac and non-cardiac factors, in order to prevent DNHF as well as non-HF death as a competing risk., Trial Registration: clinicaltrials.gov identifier: NCT00418041., Competing Interests: Declaration of competing interest H.S. received lecture fees from Bayer Yakuhin, Ltd., (Osaka, Japan), Daiichi Sankyo Co., Ltd. (Tokyo, Japan) and Novartis Pharma K.K., (Tokyo, Japan). The Department of Evidence-based Cardiovascular Medicine, Tohoku University Graduate School of Medicine, is supported in part by the unrestricted research grants from Daiichi Sankyo Co., Ltd. (Tokyo, Japan), Bayer Yakuhin, Ltd., (Osaka, Japan), Kyowa Hakko Kirin Co., Ltd., (Tokyo, Japan), Kowa Pharmaceutical Co., Ltd., (Tokyo, Japan), Novartis Pharma K.K., (Tokyo, Japan), Dainippon Sumitomo Pharma, Co., Ltd. (Osaka, Japan), and Nippon Boehringer Ingelheim Co., Ltd. (Tokyo, Japan)., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Along with the global aging, the number of geriatric patients with acute myocardial infarction (AMI) has been increasing. However, temporal trends in the prevalence and outcomes of geriatric patients with AMI, with a special reference to heart failure (HF) on admission, remain to be elucidated., Methods: The Miyagi AMI Registry is a prospective, multicenter, and observational study. This registry was established in 1979 and has been continued for 40 years. We examined a total of 6,596 AMI patients aged ≥70 years (male/female 4,141/2,455) registered in this registry from 2005 to 2016 and divided them into 3 groups according to age [70-79 (n = 3,485), 80-89 (n = 2,601), and ≥90 years (n = 510)]., Results: Of those, 17.6% had HF (Killip class ≥ II) on admission, for which age, female sex, diabetes, and previous MI were identified as independent predictors. Importantly, the prevalence of HF on admission significantly increased in all ages during the study period (all p for trend <0.01). Despite the presence of HF on admission, primary percutaneous coronary intervention (PCI) was performed in about 70% of patients aged in their 80 s and about half of those aged ≥90 years. In each group, performance rate of primary PCI also progressively increased (all p < 0.05) irrespective of concomitant HF. However, in-hospital mortality remained unchanged. Multivariable analysis demonstrated that, even for patients with HF on admission, primary PCI was associated with improved in-hospital mortality in the younger 2 groups [adjusted odds ratios (ORs), 95% confidence intervals (CI) 0.58 (0.36-0.93) for 70s, 0.64 (0.43-0.95) for 80s, and 0.99 (0.44-2.21) for ≥90s], whereas PCI was ineffective to reduce long-term hospitalization ≥30 days in all groups [adjusted ORs (95%CI) 0.90 (0.52-1.54), 0.66 (0.38-1.14), and 0.38 (0.07-2.10)]., Conclusions: These results demonstrate that increasing prevalence of HF on admission and increasing performance of primary PCI counteract each other with resultant unchanged in-hospital outcomes in geriatric AMI patients in Japan., (Copyright © 2019. Published by Elsevier Ltd.)

Background: We have recently demonstrated that left ventricular ejection fraction (LVEF) dynamically changes over time with prognostic impacts in Stage C/D patients, namely, those who have a current or past history of heart failure (HF). However, it is unknown whether this is also the case in asymptomatic Stage B patients, namely, those who have a risk of HF, but do not have a history of HF., Methods: In our CHART-2 Study (N = 10,219), we enrolled 4005 Stage B patients and divided them into 3 groups by LVEF; preserved EF (pEF, LVEF ≥50%, N = 3526), mid-range EF (mrEF, LVEF 41-49%, N = 302), and reduced EF (rEF, LVEF ≤40%, N = 177). We examined the prognostic impacts of LVEF transitions among the 3 groups in comparison with 4477 patients with Stage C/D HF., Results: Stage B were characterized by less severe clinical status and better prognosis compared with Stage C/D. Stage B in mrEF and rEF at baseline dynamically transitioned to other groups at 1-year, whereas those in pEF unchanged; at 1-year, mrEF transitioned to pEF/rEF by 50/16%, and rEF transitioned to pEF/mrEF by 25/31%, respectively, whereas pEF transitioned to mrEF/rEF by only 3.6/0.7%, respectively, which were consistent with findings in findings with Stage C/D. Although LVEF decrease was directly associated with all-cause mortality in both the Stage B and Stage C/D with pEF, factors related to LVEF changes were different between the 2 groups., Conclusions: In Stage B, LVEF dynamically changes with prognostic impacts as in Stage C/D, whereas different determination factors may be involved in the 2 stages., Clinical Trial Registration: Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-2 (NCT00418041)., Competing Interests: Declaration of competing interest All authors declare no competing interests for the present study. Conflict of interests is shown in Supplemental files., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Although cardiac troponin and natriuretic peptide have been shown to decrease after balloon pulmonary angioplasty (BPA) with improved right ventricular afterload in chronic thromboembolic pulmonary hypertension (CTEPH), biomarkers to evaluate the effects of BPA independently of heart failure status remain to be developed., Methods: In 39 consecutive CTEPH patients including 31 who underwent BPA, we measured plasma levels of cyclophilin A (CyPA), which we demonstrated is secreted from pulmonary vascular smooth muscle cells in response to mechanical stretch and hypoxia., Results: CyPA levels were elevated in CTEPH patients (12.7, IQR: 7.6-16.0) compared with 8 thromboembolic controls with a history of venous thromboembolism (4.9, IQR: 2.4-11.2) or 18 healthy controls (4.1, IQR: 2.4-6.8) (both p< 0.05) and were linearly correlated with mean pulmonary arterial pressure (r=0.50, p = 0.0003) and pulmonary vascular resistance (r=0.32, p= 0.026). BPA reduced CyPA levels and tended to lower brain-type natriuretic peptide (BNP) levels (p< 0.01 and p = 0.07). When comparing the changes in CyPA before and after BPA in the two subgroups with higher (≥35pg/mL) and normal (<35pg/mL) BNP at baseline, CyPA decreased both in patients with higher BNP and those with normal BNP (both p< 0.05). In contrast, BNP decreased only in patients with higher BNP (p< 0.05). Also, CyPA decreased both in patients with lower (<25 kg/m 2 ) and higher (≥25kg/m 2 ) body mass index (BMI) at baseline (both p<0.05), whereas BPA tended to reduce BNP in patients with lower BMI (p = 0.12) but not in those with higher BMI (p = 0.55)., Conclusions: CyPA could be a useful biomarker to evaluate the effects of BPA even in patients with normal BNP or high BMI., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: In the current era of treatment of pulmonary hypertension (PH) in Japan, combination therapy has been frequently used thanks to the medical insurance system. Additionally, pulmonary balloon angioplasty (BPA) is widely performed for chronic thromboembolic PH (CTEPH)., Methods: To elucidate the long-term prognosis and the prognostic factors among all five subtypes of PH in this new era, we examined the current status of management of PH from November 2012 to April 2016 in the multicenter registry by the Japanese Pulmonary Circulation Society., Results: Among 1253 consecutive patients registered from 20 PH centers in Japan, we analyzed 997 patients with mean pulmonary arterial pressure ≥ 25 mmHg by right heart catheterization. Transplant-free survival at 5 years in pulmonary arterial hypertension (PAH), PH due to left-heart disease, PH due to lung diseases, CTEPH, and miscellaneous PH were 74.0, 69.3, 63.7, 92.0, and 55.3%, respectively. Of note, 32% of PAH patients were treated with double combination therapy and 42% of those with triple combination therapy, and 66% of CTEPH patients with BPA. Although PAH patients with triple combination therapy had worse hemodynamic parameters than those with other medications, triple combination therapy showed the best prognosis. BPA in CTEPH improved survival even when adjusted for the key background factors., Conclusions: In the current era of PH treatment in Japan, the five-year transplant-free survival rate in this study was 74% for PAH and 92% for CTEPH, in which active combination medical therapy for PAH and higher performance rate of BPA for CTEPH may be involved., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The benefits of antithrombotic therapy (ATT) for atrial fibrillation (AF) are occasionally offset by major bleeding complications. However, the clinical benefits and risks of ATT in AF patients, with special references to comorbidities, such as heart failure (HF), coronary artery disease (CAD), and the patterns of AF, remain to be fully elucidated., Methods: A total of 3221 consecutive AF patients from our Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (N = 10,219) were divided into 4 groups based on ATT at enrollment; no-ATT, anticoagulant alone, antiplatelet alone, and both of them (AC&AP). Then, efficacy and safety outcomes including thromboembolic events, major bleeding, and mortality were evaluated among the 4 groups., Results: Anticoagulant monotherapy was associated with reduced risk of ischemic stroke in patients with but not in those without HF, CAD, or non-paroxysmal AF. Although there was no significant difference in major bleeding among the 4 groups, a composite of thromboembolism and major bleeding occurred more frequently in the AC&AP group, even in combination with anticoagulants and single antiplatelet therapy, indicating that the combination therapy is more harmful than anticoagulant monotherapy for AF patients, especially for those with HF or CAD. Lastly, no-ATT group was associated with worse prognosis compared with other 3 groups., Conclusions: These results indicate that ATT is beneficial for AF patients particularly for those with HF, CAD, or non-paroxysmal AF and that among ATT, anticoagulant monotherapy may be most profitable for both clinical benefits and risks for AF patients., (Copyright © 2019. Published by Elsevier B.V.)

Background: Although recent reports showed that left ventricular ejection fraction (LVEF) is a prognostic factor in patients with cardiac sarcoidosis (CS), advances in diagnostic imaging have enabled us to detect CS patients with preserved LVEF in the early stage of the disorder. In the present study, we examined the prognosis and risk stratification in CS patients with preserved LVEF., Methods and Results: We retrospectively examined 91 consecutive CS patients at our hospital from October 1998 to December 2015 (age, 57±11 years; male/female, 25/66) for the relationship between LVEF and major adverse cardiac events (MACE), including ventricular tachycardia and fibrillation (VT/VF), heart failure (HF) admission, complete atrioventricular block, and all-cause death. CS patients with preserved LVEF (≥50%), as compared with those with reduced LVEF (<50%), showed significantly higher survival free from total MACE or VT/VF (log-rank p<0.001) and significantly smaller LV myocardial damaged area as evaluated by magnetic resonance imaging (MRI) (p<0.001). Although CS patients with preserved LVEF had a good prognosis in general, persistent right ventricular (RV) pacing and reduced EF were significant predictors for MACE after 1 year from introduction of steroid therapy (hazard ratio, 5.25; 95% confidence interval, 1.31-22.50, p=0.020, hazard ratio, 9.01; 95% confidence interval, 2.45-72.09; p=0.001). Patients with the 2 factors (LVEF reduction rate >13.9% per year and persistent RV pacing) had significantly higher risk for MACE, compared with those without them (log-rank p<0.001)., Conclusion: The present study demonstrates that CS patients with preserved LVEF have better long-term prognosis than those with reduced LVEF in general. However, we should carefully follow them up, since chronological reduction in LVEF and persistent RV pacing could predict worse prognosis in those patients., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Intra-procedural myocardial ischemia as an iatrogenic complication still remains a critical issue in contemporary interventional cardiology. The aim of this study was to examine the usefulness of fasudil, a selective Rho-kinase inhibitor, for percutaneous coronary intervention (PCI)-related myocardial ischemia., Methods: Among 448 PCI sessions performed between October 2015 and December 2017, we retrospectively examined 36 patients (69.0 ± 9.1 [SD] yrs., M/F 26/10) who underwent intracoronary administration of fasudil during a procedure to resolve myocardial ischemia that was resistant to intracoronary nitrate administration., Results: The refractory myocardial ischemia was caused by distal embolization (69%), enhanced vasoconstriction at distal site of chronic total occlusion (11%), coronary spasm (11%), and coronary dissection (8%), most of which occurred immediately after balloon or stent dilatation. Intracoronary fasudil significantly improved corrected TIMI frame count (from 37 [30-56] to 24 [12-36]) and TIMI flow grade (from 2 [1-2.5] to 3 [2-3]) (both P < 0.001). Finally, 86% of all subjects successfully obtained TIMI flow grade 3 at the end of the procedure. Intracoronary fasudil tended to be more effective in patients with an attenuated plaque detected by intravascular ultrasound. Importantly, among the 19 elective cases, fasudil successfully prevented 17 patients from developing post-procedure myocardial infarction. Although fasudil-induced transient hypotension requiring a vasopressor was noted in 22% of the subjects, no other adverse effects were noted., Conclusions: These results indicate that fasudil is a useful and safe therapeutic option for PCI-related myocardial ischemia refractory intracoronary nitrate., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by organic thrombotic obstructions in the pulmonary arteries with reduced pulmonary vascular reserve. This study aimed to examine whether postural changes in ventilatory gas analysis parameters are useful for assessing pulmonary hemodynamics in patients with CTEPH., Methods: A total of 44 patients with newly diagnosed CTEPH (CTEPH group), 33 patients with improved CTEPH (mean pulmonary arterial pressure [mPAP] <25 mm Hg), and 25 controls were enrolled. Patients with improved CTEPH referred to patients without residual PH who were previously diagnosed with CTEPH and already received optimal therapies. Various pulmonary function parameters were examined in supine and sitting positions, and postural changes were calculated (Δ[supine - sitting]). In 32 patients with CTEPH, we examined hemodynamic and ventilatory gas analysis parameters before the first balloon pulmonary angioplasty (BPA) and during follow-up., Results: Patients with CTEPH had significantly lower supine end-tidal carbon dioxide pressure (P ET CO 2 ) and ΔP ET CO 2 than controls (both P < 0.001), and these parameters were significantly correlated with mPAP (R 2  = 0.507, P < 0.0001 and R 2  = 0.470, P < 0.001, respectively). Supine P ET CO 2 and ΔP ET CO 2 were significantly lower in patients with improved CTEPH than in controls (both P < 0.001). Hemodynamic and echocardiographic parameters were comparable in both groups. Furthermore, significant correlation between the change in mPAP and change in supine P ET CO 2 by BPA was noted (R 2  = 0.478, P < 0.001)., Conclusion: These results indicate that postural changes in ventilatory gas analysis parameters are useful and non-invasive method for the evaluation of mPAP, which is one of the hemodynamic parameters of CTEPH severity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Dilated cardiomyopathy caused by lamin A/C gene (LMNA) mutation is complicated with atrioventricular (AV) conduction disturbances, malignant ventricular arrhythmias, and progressive severe heart failure. Radiofrequency catheter ablation (RFCA) of ventricular tachycardia (VT) has been reported to be challenging due to the high recurrence rate in patients with LMNA-related cardiomyopathy. However, electrophysiological and histopathological characteristics of VT substrate remain to be fully elucidated., Methods and Results: We experienced 6 familial patients with LMNA-related cardiomyopathy in 3 pedigrees (6 males, 43.7±4.5 [SD] years). All patients had first VT attack at 50±6.6 [SD] years of age, and 4 underwent RFCA for incessant VT. Their electrocardiograms during VT showed similar QRS morphologies, characterized by an inferior axis, SR pattern in aVR, and QS pattern in aVL, suggesting the origin of the basal anterior ventricle. Indeed, the VTs had multiple exits around the basal anterior ventricular septum in all RFCA cases. Although we performed multiple RFCA procedures including epicardial ablation and surgical cryoablation, all cases experienced VT recurrences in 4.5±6.4 [SD] months after last procedure. All patients developed end-stage heart failure with frequent VT events, and died at 59.5±3.6 years of age (severe heart failure in 5 and lung disease in 1). In three autopsy cases with RFCA, fibrofatty degeneration was noted in the AV node. In addition, in the deep basal ventricular septum, inhomogenous fibrotic degenerated tissue was noted beyond the reach of RF lesions., Conclusions: These results demonstrate that patients with LMNA-related cardiomyopathy are characterized by VTs refractory to RFCA probably because of the deep intramural focus at the basal ventricular septum, resulting in poor prognosis with progressive severe heart failure despite all available optimized therapies. Thus, we should consider heart transplantation in their early 50s when several VT events begin to occur., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Several studies have reported that C-reactive protein (CRP), an inflammatory biomarker, predicts cardiovascular events independently of low-density lipoprotein cholesterol levels. However, no study examined whether temporal changes in CRP levels are associated with clinical events in patients with previous myocardial infarction (MI)., Methods and Results: We examined 2184 consecutive patients with previous MI and CRP data at baseline in the Chronic Heart Failure Registry and Analysis in the Tohoku district-2 (CHART-2) Study. During the median 6.4 years follow-up, 592 all-cause, 245 cardiovascular, and 273 non-cardiovascular deaths occurred. Patients with CRP ≥ 2.0 mg/L at baseline had significantly increased incidence of all-cause (hazard ratio (HR) 1.68, P < 0.001) and non-cardiovascular death (HR 1.86, P < 0.001), compared with those with CRP < 2.0 mg/L. Temporal changes in CRP levels were associated with prognosis; among patients with CRP ≥ 2.0 mg/L at baseline, those with CRP ≥ 2.0 mg/L at 1-year had significantly increased incidence of all-cause (HR 2.12, P < 0.001), cardiovascular (HR 2.31, P < 0.001), and non-cardiovascular death (HR 2.29, P < 0.001). Among patients with CRP < 2.0 mg/L at baseline, those with CRP ≥ 2.0 mg/L at 1-year had significantly increased incidence of all-cause (HR 1.76, P < 0.001) and cardiovascular death (HR 2.10, P = 0.001). These results remained significant after adjusted with the inverse probability of treatment weighted models using propensity sore. Furthermore, as compared with patients with CRP < 2.0 mg/L at both baseline and 1-year, those with CRP ≥ 2.0 mg/L at both baseline and 1-year had increased incidence of all-cause, cardiovascular, and non-cardiovascular death., Conclusions: These results provide the evidence that temporal increases in CRP levels are associated with increased clinical events in patients with previous MI., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Possible ethnic differences in clinical characteristics and long-term prognosis of contemporary patients with vasospastic angina (VSA) remain to be elucidated., Methods and Results: The Japanese Coronary Spasm Association (JCSA) conducted an international, prospective, and multicenter registry study for VSA patients. A total of 1457 VSA patients (Japanese/Caucasians, 1339/118) were enrolled based on the same diagnostic criteria. Compared with Caucasian patients, Japanese patients were characterized by higher proportions of males (68 vs. 51%) and smoking history (60 vs. 49%). Japanese patients more often had angina especially during the night and early morning hours, compared with Caucasians. Ninety-five percent of Japanese and 84% of Caucasian patients underwent pharmacological provocation test. Importantly, no significant differences in the patterns of coronary spasm were apparent, with diffuse spasm most frequently noted in both ethnicities. The prescription rate of calcium-channel blockers was higher in Japanese (96 vs. 86%), whereas the uses of nitrates (46 vs. 59%), statins (43 vs. 65%), renin-angiotensin-system inhibitors (27 vs. 51%), and β-blockers (10 vs. 24%) were more common in Caucasian patients. Survival rate free from major adverse cardiac events (MACE) was slightly but significantly higher in Japanese than in Caucasians (86.7 vs. 76.6% at 5 years, P < 0.001). Notably, multivariable analysis revealed that the JCSA risk score correlated with MACE rates not only in Japanese but also in Caucasian patients., Conclusion: These results indicate that there are ethnic differences in clinical profiles and long-term prognosis of contemporary VSA patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Although several factors, including heart failure (HF) and inflammation, are known to increase the incidence of cancer, it remains unknown whether HF may increase cancer mortality, especially with a reference to inflammation., Methods and Results: We examined 8843 consecutive cardiovascular patients without a prior history of cancer in our CHART-2 Study (mean 68 yrs., female 30.9%). As compared with patients without HF (Stage A/B, N = 4622), those with HF (Stage C/D, N = 4221) were characterized by higher prevalence of diabetes, previous myocardial infarction, atrial fibrillation, and stroke. During the median 6.5-year follow-up (52,675 person-years), 282 cancer deaths occurred. HF patients had significantly higher cancer mortality than those without HF in both the overall (3.7 vs, 2.8%, hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.12-1.79, P = 0.004) and the propensity score-matched cohorts (HR 1.46, 95%CI 1.10-1.93, P = 0.008), which was confirmed in the competing risk models. The multivariable Cox proportional hazard model in the matched cohort showed that HF was associated with increased cancer mortality in patients with C-reactive protein (CRP) ≥ 2.0 mg/L (HR 1.87, 95%CI 1.18-2.96, P = 0.008) at baseline, but not in those with CRP < 2.0 mg/L (HR 0.89, 95%CI 0.54-1.45, P = 0.64) (P for interaction = 0.03). Furthermore, temporal changes in CRP levels were associated with cancer death in the overall cohort; HF patients with CRP ≥ 2.0 mg/L at both baseline and 1-year had significantly increased cancer death, while those with CRP ≥ 2.0 mg/L at baseline and < 2.0 mg/L at 1-year not., Conclusions: These results provide the first evidence that HF is associated with increased cancer death, especially when associated with prolonged inflammation., (Copyright © 2019. Published by Elsevier B.V.)

Background: It is important to identify the risk factors and localization of silent cerebral infarction (SCI), especially in younger patients with atrial fibrillation (AF)., Objective: The purpose of this study was to examine the characteristics and risk factors for SCI in AF patients, with particular attention to localization of SCI., Methods: The study enrolled 286 consecutive neurologically asymptomatic patients who underwent AF ablation from January 2014 to July 2017 (age 61.7 ± 10.2 [SD] years; 208 male and 78 female). All patients underwent magnetic resonance imaging (MRI) before ablation., Results: SCIs were classified independently by 2 radiologists as follows: cardiogenic SCI in 19 (10.6%), lacunar SCI in 13 (8.9%), undetermined causes in 6 (1.6%), and no SCI in 248 (controls, 78.7%). Importantly, no patients with CHA 2 DS 2 -VASc score 0 had SCI on MRI. In univariable analysis, significant risk factors for lacunar SCI included age (P = .007), hypertension (P = .037), congestive heart failure (P = .040), left atrial (LA) diameter (P = .013), and cardio-ankle vascular index (P = .004). In multivariable analysis, significant risk factors for cardiogenic SCI were AF duration (odds ratio [OR] 1.01; 95% confidence interval [CI] 1.00-1.02; P = .038), ankle-brachial pressure index (OR 0.002; 95% CI 0-0.68; P = .030), and LA abnormality (OR 8.99; 95% CI 2.78-31.00; P <.001), defined by the presence of spontaneous echo contrast and/or decreased LA appendage emptying velocity., Conclusion: The study results indicate that among AF patients, SCIs localized in the cerebral cortex and cerebellum are frequently noted, for which cardiogenic mechanisms may be mainly involved; CHA 2 DS 2 -VASc score could be useful for screening SCI; and LA abnormality is the specific marker for cardiogenic SCI, providing useful information for risk stratification of SCI., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Few simple risk models, without echocardiography have been developed for patients with heart failure (HF) and preserved left ventricular ejection fraction (LVEF) (HFpEF)., Methods: To develop a risk score to predict all-cause death for HFpEF patients, we examined 1277 HF patients with LVEF ≥50% and BNP ≥100 pg/ml in the CHART-2 Study, a large-scale prospective cohort study for HF in Japan. We selected the optimal subset of covariates for the score with Cox proportional hazard models and random survival forests (RSF)., Results: During the median 5.7-year follow-up, 576 deaths occurred. Cox models and RSF analyses consistently indicated age ≥75 years, albumin <3.7 g/dl, anemia, BMI <22 kg/m 2 , BNP ≥300 pg/ml (or NT-proBNP ≥1400 pg/ml), and BUN ≥25 mg/dl, as the important 6 prognostic variables. Incorporating these 6 variables, we developed a scoring system (3A3B score, with 2 points given to age ≥75 years and 1 point to the others based on the hazard ratios. The discrimination ability of the risk score was excellent (c-index 0.708). Regarding model goodness-of-fit, the overall gradient in 5-year risk was well captured by the score. The predictive accuracy of the 3A3B score was confirmed in the external validation cohorts from the TOPCAT trial (N = 835, c-index 0.652) and the ASIAN-HF registry (N = 170, c-index 0.741)., Conclusions: We developed a simple risk score to predict long-term prognosis of HFpEF patients. The 3A3B score, comprising 6 commonly available parameters in daily practice, has potential utility in the risk stratification and management of HFpEF patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Self-care behaviors (ScB) are associated with symptoms and outcomes in patients with heart failure (HF). However, little is known about gender differences in the prognostic relevance of ScB in HF patients., Methods: We examined gender differences in ScB of HF patients regarding its prognostic associations with mortality and HF hospitalization with a reference to ScB dimensions. The European Heart Failure Self-Care Behavior Scale (EHFScBS) was used to evaluate ScB in 2233 patients with Stage C/D HF in the CHART-2 Study., Results: Male patients (n=1583) were younger (71 vs. 73 yrs) and had lower ScB (median 33 vs. 31) (all p<0.001) than females (n=650). During the median follow-up of 2.57 years, patients with high ScB (score 12-32, n=1090), as compared with low ScB patients (score 33-60, n=1143), had significantly increased all-cause mortality in males [adjusted hazard ratio (aHR) 1.44, p=0.02] but not in females (aHR 0.80, p=0.40) (p for interaction 0.02), while ScB was not significantly associated with incidence of HF hospitalization in both genders. Among the 3 dimensions in EHFScBS, complying with regimen was associated with decreased mortality in females, but not in males (p for interaction 0.003), while asking for help was related with increased incidence of HF hospitalization in males (aHR 1.34, p=0.072) but not in females (aHR 0.98, p=0.931) (p for interaction 0.048)., Conclusions: There were gender differences in the prognostic relevance of self-care with mortality and incidence of HF hospitalization, suggesting that self-care should be implemented considering gender differences to improve prognosis., (Copyright © 2018 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Although B-type natriuretic peptide (BNP) and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) are released in equimolar proportions, their values differ depending on clinical conditions. A useful conversion formula between BNP and NT-proBNP remains to be developed for the clinical use., Aim: To develop a conversion formula from BNP to NT-proBNP., Methods: In the derivation cohort, 923 patients with chronic heart failure, in whom both BNP and NT-proBNP values were available, were enrolled from our SUPPORT (Supplemental Benefit of ARB in Hypertensive Patients with Stable Heart Failure using Olmesartan) trial. The validation cohort included 1154 consecutive patients with or at risk of cardiovascular diseases, in whom both BNP and NT-proBNP values were measured simultaneously at Tohoku University Hospital. We regressed log 10 NT-proBNP onto log 10 BNP and factors influencing BNP and NT-proBNP values., Results: We adopted the model with the smallest Akaike information criterion consisting of log 10 BNP, age, sex, BMI, creatinine clearance (CCr), hemoglobin, and atrial fibrillation (AF). As compared with the previously reported conversion formulas, the present conversion formula utilized non-linear transformation by spline function, and exhibited the strongest correlation between actual and calculated values of NT-proBNP (r = 0.928). The root mean squared error (RMSE) of the present conversion formula was smallest compared with the previously reported conversion formulas, indicating that this formula most effectively converts BNP values to NT-proBNP values., Conclusions: We have developed a useful conversion formula from BNP to NT-proBNP values, using age, sex, BMI, CCr, hemoglobin, and AF, which could be widely used in daily clinical practice., (Copyright © 2018. Published by Elsevier B.V.)

Background: Complete revascularization with PCI is not always achieved in patients with ischemic HF. Therefore, this study aimed to elucidate the prognostic impact of residual coronary stenosis (RS) after percutaneous coronary intervention (PCI) in patients with ischemic heart failure (HF)., Methods: We analyzed a total of 1307 patients with symptomatic HF and a history of PCI registered in our Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study. RS that was defined as the presence of ≥70% luminal stenosis in major coronary arteries at the last coronary angiography., Results: Among the study population, 851 patients (65.1%) had RS. During a median follow-up period of 3.2 years, patients with RS had higher all-cause mortality than those without it even after propensity score matching (21.9 vs. 11.6%, log-rank P = 0.027). Multivariable Cox hazard analysis also showed the negative impact of RS on all-cause death in ischemic HF patients [hazard ratio (HR):1.62, 95% confidence interval (CI): 1.07-2.46, P = 0.024]. Importantly, when divided all subjects into three subgroups by left ventricular ejection fraction (LVEF) [LVEF < 40% (HFrEF), LVEF 40-49% (HFmrEF), and LVEF ≥ 50% (HFpEF)], inverse probability of treatment weighted method provided a similar result that RS after PCI was an independent risk factor for death in the HFpEF [HR(95%CI); 1.94(1.22-3.09), P < 0.01] and HFmrEF [4.47(1.13-14.98), P < 0.01] groups, but not in the HFrEF group [1.20(0.59-2.43), P = 0.62]., Conclusions: These results indicate that RS after PCI could aggravate long-term prognosis of ischemic HF patients with moderate- to well-preserved EF, but not those with reduced EF., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Therapeutic focused-ultrasound to the hippocampus has been reported to exert neuroprotective effects on dementia. In the present study, we examined whether the whole-brain LIPUS (low-intensity pulsed ultrasound) therapy is effective and safe in 2 mouse models of dementia (vascular dementia, VaD and Alzheimer's disease, AD), and if so, to elucidate the common underlying mechanism(s) involved., Methods: We used bilateral carotid artery stenosis (BCAS) model with micro-coils in male C57BL/6 mice as a VaD model and 5XFAD transgenic mice as an AD model. We applied the LIPUS therapy (1.875 MHz, 6.0 kHz, 32cycles) to the whole brain., Results: In both models, the LIPUS therapy markedly ameliorated cognitive impairments (Y-maze test and/or passive avoidance test) associated with improved cerebral blood flow (CBF). Mechanistically, the LIPUS therapy significantly increased CD31-positive endothelial cells and Olig2-positive oligodendrocyte precursor cells (OPCs) in the VaD model, while it reduced Iba-1-positive microglias and amyloid-β (Aβ) plaque in the AD model. In both models, endothelium-related genes were significantly upregulated in RNA-sequencing, and expressions of endothelial nitric oxide synthase (eNOS) and neurotrophins were upregulated in Western blotting. Interestingly, the increases in glia cells and neurotrophin expressions showed significant correlations with eNOS expression. Importantly, these beneficial effects of LIPUS were absent in eNOS-knockout mice., Conclusions: These results indicate that the whole-brain LIPUS is an effective and non-invasive therapy for dementia by activating specific cells corresponding to each pathology, for which eNOS activation plays an important role as a common mechanism., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: The EXPAND study examined the real-world efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism (SE) in Japanese patients with non-valvular atrial fibrillation (NVAF)., Methods and Results: This multicenter, prospective, non-interventional, observational, cohort study was conducted at 684 medical centers in Japan. A total of 7141 NVAF patients ≥20 years of age (mean, 71.6 ± 9.4 years) who were being or about to be treated with rivaroxaban (10 mg/day, 43.5%; 15 mg/day, 56.5%) were followed for an average of 897.1 (±206.8) days with a high follow-up rate (99.65%). The mean CHADS 2 score at baseline was 2.1 (1.3) (0-1, 37%; 2, 29%; ≥3, 34%). The total incidence rate of symptomatic stroke and SE (primary efficacy endpoint) was 1.0%/year, and 0.5%, 0.9%, and 1.7%/year for those with CHADS 2 scores of 0-1, 2, and ≥3, respectively. Cumulative incidence rates for major bleeding (primary safety endpoint) and non-major bleeding (secondary safety endpoint) were 1.2%/year and 4.9%/year, respectively. Differences were noted between new and current users only for major bleeding event rate (1.7% vs. 1.1%/year, P = 0.0024). Comparisons with previous studies suggested that rivaroxaban is effective and safe for low-risk patients (0-1 CHADS 2 ), as shown for warfarin in the XANTUS international prospective post-marketing study., Conclusions: The EXPAND study demonstrated that low dosages of rivaroxaban for Japanese NVAF patients in real-world clinical practice, including those with CHADS 2 scores 0-1, resulted in low rates of stroke and SE, and major and non-major bleeding., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Myocardial bridge (MB) is a myocardial bundle through which coronary segment tunnels and could compress coronary arteries causing myocardial ischemia. However, the characteristic structural findings of MB remain to be fully elucidated. Recently, we demonstrated that optical coherence tomography (OCT) enables us to visualize adventitial vasa vasorum (VV) formation in humans. In this study, we examined adventitial VV formation at the coronary segment with MB in humans using OCT., Methods: We examined 15 consecutive patients with suspected angina pectoris and MB in the left anterior descending (LAD) coronary arteries but no angiographic coronary stenosis. MB was detected on coronary angiography as a segment with milking effect. We performed intracoronary OCT imaging along the entire LAD. Morphometric analysis was performed at MB and proximal/distal segments at every 1mm., Results: OCT examination showed the absence of adventitial VV formation at MB in the LAD, while VV was clearly noted at both the proximal and distal reference segments. Adventitial VV area was significantly less at MB compared with the proximal or distal references., Conclusions: These results with OCT imaging indicate that coronary segments with MB lack adventitial VV formation in humans, suggesting that MB could influence morphological and functional changes of the coronary artery., (Copyright © 2017. Published by Elsevier B.V.)

Standardization of diagnostic criteria for ischemic symptoms due to coronary microvascular dysfunction (CMD) is needed for further investigation of patients presenting with anginal chest pain consistent with "microvascular angina" (MVA). At the annual Coronary Vasomotion Disorders International Study Group (COVADIS) Summits held in August 2014 and 2015, the following criteria were agreed upon for the investigative diagnosis of microvascular angina: (1) presence of symptoms suggestive of myocardial ischemia; (2) objective documentation of myocardial ischemia, as assessed by currently available techniques; (3) absence of obstructive CAD (<50% coronary diameter reduction and/or fractional flow reserve (FFR) >0.80) (4) confirmation of a reduced coronary blood flow reserve and/or inducible microvascular spasm. These standardized criteria provide an investigative structure for mechanistic, diagnostic, prognostic and clinical trial studies aimed at developing an evidence base needed for guidelines in this growing patient population. Standardized criteria will facilitate microvascular angina registries and recruitment of suitable patients into clinical trials. Mechanistic research will also benefit from the implementation of standardized diagnostic criteria for MVA., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: We and others have previously reported that the Great East Japan Earthquake (GEJE) caused a significant but transient increase in cardiovascular diseases and deaths in the disaster area. However, it remains to be examined whether the GEJE had a long-term prognostic influence in large-scale cohort studies. This point is important when analyzing the data before and after the GEJE in the cohort studies in the disaster area., Methods: We examined 8676 patients registered in our Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (N=10,219) between 2006 and 2010 and were alive after March 10, 2011., Results: There were 48 GEJE-related deaths, causing a sharp and transient increase in all-cause death within a month after the GEJE. However, after excluding the GEJE-related deaths, the cubic polynomial spline smoothing showed no significant increase in all-cause death, heart failure admission, non-fetal acute myocardial infarction, or non-fetal stroke during the median 3-year follow-up after the GEJE. The extrapolation curves beyond the GEJE, which were obtained by the parametric survival models based on the survival data censored on the GEJE, were not significantly different from the Kaplan-Meier curves estimating the survival functions of deaths and cardiac events during the total follow-up period without considering the impacts of the GEJE. Furthermore, the multivariate Cox proportional hazard model applied to the matched cohort of the baseline data and the data after the GEJE showed no significant differences in the impacts of prognostic factors on all-cause mortality before and after the GEJE., Conclusions: These results indicate that the GEJE had no significant long-term prognostic impact after the earthquake in cardiovascular patients in the disaster area., (Copyright © 2016. Published by Elsevier Ltd.)

Background: We previously demonstrated that heart failure (HF) was one of the major causes of death in arrhythmogenic right ventricular cardiomyopathy (ARVC). The purpose of this study was to elucidate the clinical impact and risk factors of HF in patients with ARVC., Methods and Results: We evaluated cardiac adverse outcomes including HF in 113 consecutive patients with ARVC (85 men, mean age: 44±15years). During a median follow-up of 10.0years (interquartile range: 5.2 to 15.7years), 29 patients (26%) were hospitalized for progressive HF. The patients with one or more episodes of HF hospitalization had about a 10-fold increased incidence of cardiac death (14/29 [48%] vs. 4/84 [4.7%], p<0.0001). Left ventricular ejection fraction (LVEF) and right ventricular ejection fraction (RVEF) were significantly lower in the patients with HF hospitalization compared to the patients without HF hospitalization (LVEF, 45±15 vs. 54±13%, p=0.001; RVEF, 26±10 vs. 33±11%, p=0.003, respectively). Regarding the ECG findings, the prevalence of first-degree atrioventricular block (AVB, PR interval >200ms) and epsilon waves were significantly higher in patients with HF hospitalization than those without HF hospitalization (first-degree AVB, 14/29 [48%] vs. 11/84 [13%], p<0.0001; epsilon waves, 10/29 [34%] vs. 12/84 [14%], p=0.02). In multivariate analysis, first-degree AVB at baseline was the strongest independent risk factor for HF hospitalization in patients with ARVC (hazard ratio 4.24, 95% confidence interval 1.79-10.47, p=0.0011)., Conclusion: HF hospitalization has a significant relation with malignant clinical course in ARVC patients. First-degree AVB was an independent determinant for increased risk of HF hospitalization., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to examine which component of drug-eluting stents (DES) plays a major role in enhanced coronary vasoconstricting responses after DES implantation in pigs., Background: Recent studies have reported unremitting angina due to vasomotion abnormalities even after successful DES implantation. However, it remains to be elucidated which component of DES (metal stent, polymer coating, or antiproliferative drug) is responsible for DES-induced coronary hyperconstricting responses., Methods: We developed poly-dl-lactic acid and polycaprolactone (PDLLA-PCL) copolymer technology with higher biocompatibility that is resorbed within 3 months. Four types of coronary stents were made: 1) a stent with polylactic acid (PLA) polymer coating containing antiproliferative drug (P1+D+); 2) a stent with PLA polymer coating alone without any drug (P1+D-); 3) a stent with novel PDLLA-PCL polymer coating alone (P2+D-); and 4) a bare metal stent (P-D-). The 4 stents were randomly deployed in the left anterior descending and left circumflex coronary arteries in 12 pigs., Results: After 1 month, coronary vasoconstriction by intracoronary serotonin was enhanced at P1+D+ and P1+D- stent edges compared with P2+D- and P-D- stent edges and was prevented by a specific Rho-kinase (a central molecule of coronary spasm) inhibitor, hydroxyfasudil. Immunostainings showed that inflammatory changes and Rho-kinase activation were significantly enhanced at P1+D+ and P1+D- sites compared with P2+D- and P-D- sites. There were significant positive correlations between the extent of inflammation or Rho-kinase expression/activation and that of coronary vasoconstriction., Conclusions: These results indicate the important roles of PLA polymer coating in DES-induced coronary vasoconstricting responses through inflammatory changes and Rho-kinase activation in pigs in vivo, which are ameliorated by PDLLA-PCL copolymers., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)