Background: Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor composed of a constitutively expressed β subunit (HIF-1β) and an oxygen-dependent α subunit (HIF-1α). HIF-1α has an important protective effect on the pathophysiology underlying coronary artery disease (CAD). However, the association between serum HIF-1α levels and incident heart failure (HF) in patients with stable CAD is unknown. Methods and Results: Serum levels of HIF-1α were measured in 1,308 patients with stable CAD with no history of HF. The primary outcome was HF hospitalization. The secondary outcomes were cardiovascular (CV) death and a composite of HF hospitalization or CV death. Patients were divided into 5 groups according to HIF-1α levels; below the sensitivity (Q0, <30 pg/mL) and quartiles of measurable HIF-1α levels (Q1, 31-119; Q2, 123-285; Q3, 291-765; Q4, 774-4131 pg/mL). Patients were followed up over a 6-year period. During the follow-up, 121 (9.3%) patients developed HF hospitalization, 89 (6.8%) died of CV diseases, and 181 (13.8%) developed a composite of HF hospitalization or CV death. After adjustment for potential clinical confounders and established CV biomarkers (i.e., N-terminal pro-brain natriuretic peptide, high-sensitivity cardiac troponin I, and high-sensitivity C-reactive protein), the associations between HIF-1α levels and outcomes were not linear: an adjusted hazard ratio (aHR) was consistently low and similar in Q2 and Q3 (v.s. Q0); there were no significant differences in aHRs between Q0 and Q1 for all outcomes; and an aHR (v.s. Q0) was significantly higher in Q4 for HF hospitalization, but not for CV death or a composite of HF hospitalization or CV death (Fig.1). Thus, we combined Q2 and Q3 into the reference group, and combined Q0 and Q1 thereafter. After the reanalysis, serum HIF-1α levels exhibited J-shaped associations with HF hospitalization and a composite of HF hospitalization and CV death, but not with CV death: the high HIF-1α level (Q4) was significantly associated with HF hospitalization and a composite of HF hospitalization and CV death, but not with CV death, while the low HIF-1α level (Q0-1) was significantly associated with a composite of HF hospitalization and CV death, but not with HF hospitalization or CV death (Fig. 2). Conclusions: We first demonstrated that serum HIF-1α levels exhibited a J-shaped association with the risk of incident HF in stable CAD.

Background: Vascular endothelial growth factor D (VEGF-D) is a secreted glycoprotein that can promote lymphangiogenesis and angiogenesis. We previously demonstrated that serum levels of VEGF-D are associated with all-cause mortality in patients with suspected or known coronary artery disease (CAD). However, sex differences in the associations of VEGF-D with all-cause and cause-specific mortality in those patients are unclear. Methods: Serum levels of VEGF-D were measured in 2,418 patients (1,624 men and 794 women) with suspected or known CAD. The outcomes were all-cause death, cardiovascular (CV) death, non-CV death, cancer death, and other non-CV death. Patients were followed up over a 6-year period. Results: During the follow-up, 391 men and 145 women died of any cause, 120 men and 46 women died of CV diseases, 241 men and 85 women died of non-CV diseases, 102 men and 26 women died of cancer, and 139 men and 59 women died of other non-CV diseases. After adjustment for potential clinical confounders and established CV biomarkers (i.e., N-terminal pro-brain natriuretic peptide, high-sensitivity cardiac troponin I, and high-sensitivity C-reactive protein), log-transformed (Ln-) VEGF-D levels were significantly associated with all-cause death (adjusted hazard ratio [aHR] for 1-SD increase, 1.42; 95% confidence interval [CI], 1.10–1.86), non-CV death (aHR, 1.60; 95% CI, 1.15–2.28), and other non-CV death (aHR, 2.00; 95% CI, 1.31–3.09), but not with CV death (aHR, 1.21; 95% CI, 0.75–2.05) or cancer death (aHR, 1.15; 95% CI, 0.71–2.14), in women; and not significantly associated with all-cause death (aHR, 0.94; 95% CI, 0.83–1.06), CV death (aHR, 0.92; 95% CI, 0.73–1.17), non-CV death (aHR, 0.91; 95% CI, 0.78–1.05), cancer death (aHR, 0.89; 95% CI, 0.71–1.12), or other non-CV death (aHR, 0.90; 95% CI, 0.74–1.08), in men. The addition of Ln-VEGF-D to the model with potential clinical confounders and established CV biomarkers significantly improved the prediction of all-cause death (continuous net reclassification improvement, 0.184; 95% CI, 0.005–0.362; P=0.045; integrated discrimination improvement, 0.012; 95% CI, 0.003–0.022; P=0.012), but not that of CV death, non-CV death, cancer death, or other non-CV death, in women, while Ln-VEGF-D did not significantly improve the prediction of any outcomes in men. Conclusions: In patients with suspected or known CAD, serum levels of VEGF-D significantly predicted all-cause mortality in women, but not in men.

Background: Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor composed of a constitutively expressed β subunit (HIF-1β) and an oxygen-dependent α subunit (HIF-1α). HIF-1α has an important protective effect on the pathophysiology underlying coronary artery disease (CAD). However, the association between serum HIF-1α levels and mortality in patients with suspected or known CAD is unknown. Methods and Results: Serum levels of HIF-1α were measured in 2,418 patients with suspected or known CAD using a commercially available enzyme-linked immunosorbent assay kit (sensitivity, 30 pg/mL). The outcomes were all-cause death, cardiovascular (CV) death, and non-CV death. Patients were divided into 5 groups according to HIF-1α levels; below the sensitivity (Q0, <30 pg/mL) and quartiles of measurable HIF-1α levels (Q1, 31-127; Q2, 128-303; Q3, 307-765; Q4, 774-4131 pg/mL). Patients were followed up over a 6-year period. During the follow-up, 536 (22.2%) deaths occurred, including 166 (6.9%) CV deaths, 326 (13.5%) non-CV deaths, and 44 (1.8%) undetermined deaths. At baseline, HIF-1α levels were significantly and inversely associated with the rate of current smoker (P<0.001), and showed significant U-shaped associations with age (P=0.016) and high-sensitivity C-reactive protein levels (P<0.001). Interestingly, HIF-1α levels exhibited U-shaped associations with incidence of all-cause, CV death, and non-CV death (Figure 1). Since the rates of incident outcomes were similar among Q1-Q3, we combined these 3 groups into the reference group for Cox proportional hazard analyses thereafter. After adjustment for potential clinical confounders and established CV biomarkers, the low HIF-1α level (Q0) was significantly associated with all-cause death (adjusted hazard ratio [aHR], 1.38; 95% confidence interval [CI], 1.02–1.91), but not with CV death (aHR, 1.12; 95% CI, 0.68–1.97) or non-CV death (aHR, 1.45; 95% CI, 0.98–2.23), while the high HIF-1α level (Q4) was not significantly associated with all-cause death (aHR, 1.12; 95% CI, 0.66–1.86), CV death (aHR, 0.76; 95% CI, 0.28–1.86), or non-CV death (aHR, 1.17; 95% CI, 0.58–2.25). Conclusions: We first demonstrated that serum HIF-1α levels exhibited a reverse J-shaped association with the risk of all-cause mortality in patients with suspected or known CAD.

Background: High circulating levels of galectin-3 are associated with all-cause and cardiovascular (CV) mortality in patients with coronary artery disease (CAD). However, the impact of anemia on the prediction of galectin-3 with cause-specific mortality in patients with suspected or known CAD is unknown. Methods: Serum levels of galectin-3 were measured in 2,418 patients with suspected or known CAD undergoing elective coronary angiography. The outcomes were all-cause death, CV death, and non-CV death. Patients were divided into 2 groups according to the presence (n=882) or absence (n=1,536) of anemia, and followed up over a 6-year period. Results: During the follow-up, 329 anemic and 207 non-anemic patients died of any cause, 116 anemic and 50 non-anemic patients died of CV diseases, and 187 anemic and 139 non-anemic patients died of non-CV diseases. After adjustment for potential clinical confounders and established CV biomarkers, log-transformed (Ln-) galectin-3 levels were significantly associated with all-cause death (hazard ratio [HR] for 1-SD increase, 1.23; 95% confidence interval [CI], 1.10–1.37) and non-CV death (HR, 1.30; 95% CI, 1.13–1.50), but not with CV death (HR, 1.16; 95% CI, 0.95–1.41) in the entire cohort; significantly associated with all-cause death (HR, 1.20; 95% CI, 1.03–1.41) and non-CV death (HR, 1.49; 95% CI, 1.20–1.85), but not with CV death (HR, 0.95; 95% CI, 0.72–1.24), in anemic patients; and significantly associated with all-cause death (HR, 1.33; 95% CI, 1.13–1.57) and CV death (HR, 1.19; 95% CI, 1.00–1.42), but not with non-CV death (HR, 1.17; 95% CI, 0.95–1.43), in non-anemic patients. We also evaluated the incremental predictive performance of galectin-3 by calculating continuous net reclassification improvement, and integrated discrimination improvement metrics. The addition of Ln-galectin-3 levels to the model with potential clinical confounders and established CV biomarkers further improved the prediction of all-cause death and non-CV death, but not that of CV death, in the entire cohort and in anemic patients, and the prediction of all-cause death and CV death, but not that of non-CV death, in non-anemic patients. Conclusions: In patients with suspected or known CAD, distinct differences were observed between anemic and non-anemic patients, in the prediction for cause-specific mortality by galectin-3 levels, which independently predicted non-CV mortality in anemic patients and CV mortality in non-anemic patients.

Background: Vascular endothelial growth factor-D (VEGF-D) is a secreted glycoprotein that can act as lymphangiogenic and angiogenic growth factors. We recently reported that VEGF-D appeared to be a prognostic marker for major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death or heart failure hospitalization (HF), in patients with HF. However, the prognostic value of changes of VEGF-D is unknown. Methods: The PREHOSP-CHF study is a nationwide prospective survey of patients with HF in Japan. Serum VEGF-D levels were measured in 203 patients (mean age, 75 years; male, 62%; mean ejection fraction, 45%) at both baseline and 6-month follow-up. We set the cut-off level of VEGF-D as 366 pg/ml, based on the ROC analysis of the entire cohort of the PREHOSP-CHF study. We defined increased VEGF-D as transition from low VEGF-D to high VEGF-D and decreased VEGF-D as transition from high to low. We investigated the association of changes of VEGF-D levels with the incidence of MACE after 6 months. Results: Mean VEGF-D levels at baseline and 6-month follow-up were 449±199 pg/ml and 519±230 pg/ml, respectively. During the 2-year follow-up, 18 patients developed MACE before 6-month follow-up, and 42 patients developed MACE after 6-month follow up. Based on levels of VEGF-D at baseline, patients with high VEGF-D showed significantly higher incidence of MACE than those without. After excluding the patients developed MACE before 6-month follow-up, 11 of 105 patients with high VEGF-D moved to the low VEGF-D group at 6-month follow-up, and 34 of 78 patients with low VEGF-D moved to the high VEGF-D group. Landmark analysis after 6 months showed that incidence of MACE was significantly higher in patients with increased VEGF-D than those without in the low VEGF-D group, and tended to be lower in patients with deceased VEGF-D than those without in the high VEGF-D group. After adjustment for ejection fraction, N-terminal B-type natriuretic peptide levels, and VEGF-D levels at baseline, increased VEGF-D were also significantly associated with the incidence of MACE after 6 months (hazard ratio per 10 pg/ml increase, 1.02; 95% confidence interval 1.00-1.03; P=0.04). Conclusions: In patients with HF, changes in VEGF-D might serve as a prognostic marker for MACE.

Introduction: Growth differentiation factor-15 (GDF-15), a stress-responsive member of the transforming growth factor ꞵ cytokine superfamily is an independent prognostic predictor in patients with heart failure (HF). GDF-15 has been also reported to be associated with cardiac cachexia and malnutrition. However the association of GDF-15 and prognosis in patients with HF according to body mass index (BMI) is unclear. Methods: The PREHOSP-CHF study is a multicenter prospective cohort study among patients with HF. A total of 1,024 patients (mean age, 75.5 years, 58.7% male) were included in the analyses. Serum levels of GDF-15, as well as N-terminal pro brain natriuretic peptide (NT-proBNP), high sensitivity troponin I (hs-cTnI), and high sensitivity C-reactive protein (hs-CRP), were measured. We divided the patients into 3 groups based on the tertile of BMI: low (≤19.9), middle (19.9<, ≤23.4), and high (>23.4). Results: The low BMI group were older, and had more female, HF with preserved ejection fraction (≥50%), and NYHA 3/4. NT-proBNP levels were higher in the low group, but hs-cTnI and hs-CRP were comparable between the 3 subgroups. Median GDF-15 levels in the low, middle and high groups were 2271, 2264, and 1888 pg/ml, respectively. During 2 years follow-up, all-cause death and major adverse cardiovascular events (MACE: cardiovascular death and HF hospitalization) occurred in 111 and 130 in the low group, 66 and 132 in the middle group, and 34 and 88 in the high group. After adjustment for clinical confounders and cardiac biomarkers, higher GDF-15 was significantly associated with the incidence of all-caused death and MACE in the entire cohort. BMI subgroup analysis revealed that higher GDF-15 was significantly associated with the incidence of all-caused death and MACE in the middle and high groups, but not in the low group (Figure). Conclusions: Among HF, higher GDF-15 was significantly associated with all-cause death and MACE especially in the middle and high BMI groups.

Background The impact of chronic kidney disease (CKD) on the prognostic utility of cardiovascular biomarkers in high-risk patients remains unclear. Methods and Results We performed a multicenter, prospective cohort study of 3255 patients with suspected or known coronary artery disease (CAD) to investigate whether CKD modifies the prognostic utility of cardiovascular biomarkers. Serum levels of cardiovascular and renal biomarkers, including soluble fms-like tyrosine kinase-1 (sFlt-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin-I (hs-cTnI), cystatin C, and placental growth factor, were measured in 1301 CKD and 1954 patients without CKD. The urine albumin to creatinine ratio (UACR) was measured in patients with CKD. The primary outcome was 3-point MACE (3P-MACE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcomes were all-cause death, cardiovascular death, and 5P-MACE defined as a composite of 3P-MACE, heart failure hospitalization, and coronary/peripheral artery revascularization. After adjustment for clinical confounders, sFlt-1, NT-proBNP, and hs-cTnI, but not other biomarkers, were significantly associated with 3P-MACE, all-cause death, and cardiovascular death in the entire cohort and in patients without CKD. These associations were still significant in CKD only for NT-proBNP and hs-cTnI. NT-proBNP and hs-cTnI were also significantly associated with 5P-MACE in CKD. The UACR was not significantly associated with any outcomes in CKD. NT-proBNP and hs-cTnI added incremental prognostic information for all outcomes to the model with potential clinical confounders in CKD. Conclusions NT-proBNP and hs-cTnI were the most powerful prognostic biomarkers in patients with suspected or known CAD and concomitant CKD.

HomeCirculationVol. 145, No. 9Efficacy and Safety of Edoxaban 15 mg According to Renal Function in Very Elderly Patients With Atrial Fibrillation: A Subanalysis of the ELDERCARE-AF Trial Open AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toOpen AccessLetterPDF/EPUBEfficacy and Safety of Edoxaban 15 mg According to Renal Function in Very Elderly Patients With Atrial Fibrillation: A Subanalysis of the ELDERCARE-AF Trial Tetsuro Yoshida, MD, PhD, Akihiro Nakamura, MD, PhD, Junichi Funada, MD, PhD, Mari Amino, MD, PhD, Wataru Shimizu, MD, PhD, Masayuki Fukuzawa, MS, Saori Watanabe, BS, Takuya Hayashi, MS, Takeshi Yamashita, MD, PhD, Ken Okumura, MD, PhD and Masaharu Akao, MD, PhD Tetsuro YoshidaTetsuro Yoshida Correspondence to Tetsuro Yoshida, MD, PhD, Department of Cardiovascular Medicine, Onga Nakama Medical Association Onga Hospital, 1725-2 Ooaza-Ozaki, Onga-cho, Onga-gun, Fukuoka 811-4342, Japan. Email E-mail Address: [email protected] https://orcid.org/0000-0002-6259-1403 Department of Cardiovascular Medicine, Onga Nakama Medical Association Onga Hospital, Japan (T. Yoshida). Search for more papers by this author , Akihiro NakamuraAkihiro Nakamura Department of Cardiology, Iwate Prefectural Central Hospital, Morioka, Japan (A.N.). Search for more papers by this author , Junichi FunadaJunichi Funada https://orcid.org/0000-0001-8810-0425 Department of Cardiology, National Hospital Organization Ehime Medical Center, Toon, Japan (J.F.). Search for more papers by this author , Mari AminoMari Amino Department of Cardiology, Tokai University, Isehara, Japan (M.A.). Search for more papers by this author , Wataru ShimizuWataru Shimizu https://orcid.org/0000-0001-9941-8973 Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan (W.S.). Search for more papers by this author , Masayuki FukuzawaMasayuki Fukuzawa Cardiovascular Group, Primary Medical Science Department, Japan Business Unit (M.F.), Daiichi Sankyo Co., Ltd., Tokyo, Japan. Search for more papers by this author , Saori WatanabeSaori Watanabe Clinical Development Department III, Development Function, Research and Development Division (S.W.), Daiichi Sankyo Co., Ltd., Tokyo, Japan. Search for more papers by this author , Takuya HayashiTakuya Hayashi The Data Intelligence Group, Data Intelligence Department, Digital Transformation Management Division (T.H.), Daiichi Sankyo Co., Ltd., Tokyo, Japan. Search for more papers by this author , Takeshi YamashitaTakeshi Yamashita https://orcid.org/0000-0002-2544-8464 Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo, Japan (T. Yamashita). Search for more papers by this author , Ken OkumuraKen Okumura Division of Cardiology, Saiseikai Kumamoto Hospital, Kumamoto, Japan (K.O.). Search for more papers by this author and Masaharu AkaoMasaharu Akao https://orcid.org/0000-0002-2348-7646 Department of Cardiology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan (M.A.). Search for more papers by this author Originally published28 Feb 2022https://doi.org/10.1161/CIRCULATIONAHA.121.057190Circulation. 2022;145:718–720The ELDERCARE-AF trial (The Edoxaban Low-Dose for Elder Care in AF Patients) demonstrated that a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding than placebo in very elderly Japanese patients with nonvalvular atrial fibrillation (NVAF) who were not appropriate candidates for standard doses of oral anticoagulants.1 In this prespecified subanalysis of the ELDERCARE-AF trial, we evaluated the association of renal function with the efficacy and safety of edoxaban 15 mg in these patients.Eligible patients were ≥80 years of age and had a history of NVAF and a CHADS2 score of ≥2. Patients had to be considered ineligible for oral anticoagulants (warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban) at the recommended therapeutic strength or approved dose for ≥1 of the following reasons: low creatinine clearance (CrCl; 15–30 mL/min), history of bleeding from a critical area or organ, low body weight (≤45 kg), continuous use of nonsteroidal anti-inflammatory drugs, and current use of an antiplatelet drug. The primary efficacy end point was the incidence of stroke or systemic embolism, and the primary safety end point was the International Society on Thrombosis and Haemostasis major bleeding. Other end points were all-cause mortality and net clinical outcome (the composite of stroke, systemic embolism, major bleeding, or all-cause mortality). Anonymized trial data will be made available at https://search.vivli.org/ to researchers on reasonable request to the corresponding author with approval by Daiichi Sankyo Co., Ltd.In this trial, 984 patients were randomly assigned to treatment (edoxaban group, n=492; placebo group, n=492) and 681 completed the trial. For this analysis, patients in the ELDERCARE-AF trial were classified into 3 subgroups on the basis of their baseline renal function: severe renal dysfunction (CrCl 15 to <30 mL/min, n=401), moderate renal dysfunction (CrCl 30–50 mL/min, n=422), and normal renal function/mild renal dysfunction (CrCl >50 mL/min, n=161). The median duration of follow-up was 466.0 days (interquartile range, 293.5–708.0). Event rates for primary end points were calculated for each renal function subgroup. The cumulative incidences of stroke or systemic embolism and major bleeding were estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to compare outcomes between the treatment groups, with the results expressed as a hazard ratio with a 95% confidence interval. Proportionality of hazards for the primary end point was confirmed by inspection of log-log survival plots. Interaction effects between treatment arms and CrCl subgroups were tested on the basis of a joint test using Wald statistics. The protocol was approved by the institute ethics committee. Written informed consent was obtained from all participants (or legal representatives for patients with cognitive impairment) before enrollment.Kaplan-Meier curves and forest plots showing the risk of stroke/systemic embolism (primary efficacy end point) and major bleeding (primary safety end point) in the edoxaban and placebo groups according to baseline CrCl subgroups are shown in the Figure. The effect of edoxaban versus placebo on stroke/systemic embolism was consistent among all CrCl subgroups (P value for interaction=0.91). The increase in major bleeding with edoxaban was nonsignificant, and there was no heterogeneity between the CrCl groups (P value for interaction=0.63). Regarding all-cause mortality, the hazard ratios of the edoxaban groups were 0.97 for the CrCl 15 to <30 mL/min subgroup, 1.12 for the CrCl 30 to 50 mL/min subgroup, and 0.86 for the CrCl >50 mL/min subgroup (P value for interaction=0.90), and those for net clinical outcome were 0.91, 0.87, and 0.77 for each CrCl subgroup, respectively (P value for interaction=0.96). No heterogeneity was observed between the groups.Download figureDownload PowerPointFigure. Relationship between stroke/systemic embolism or major bleeding and renal function in patients with nonvalvular atrial fibrillation. Kaplan-Meier curves and forest plots for stroke/systemic embolism and major bleeding in the edoxaban and placebo groups according to baseline creatinine clearance. CI indicates confidence interval; CrCl, creatinine clearance; and HR, hazard ratio.In a subanalysis of the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48), the advantage of edoxaban over warfarin was consistent across the range of renal function in patients with NVAF (the minimum renal function was CrCl 30 mL/min).2 Another study showed that edoxaban 15 mg in patients with NVAF and severe renal dysfunction (CrCl 15 to <30 mL/min) exhibited safety and plasma concentration similar to the 30-mg dose in patients with normal renal function or mild dysfunction (CrCl ≥50 mL/min).3 In the present study, edoxaban 15 mg reduced the incidence of stroke/systemic embolism regardless of the level of renal dysfunction. There was no increase in intracranial hemorrhage or fatal bleeding events in the edoxaban group.1 Thus, the use of edoxaban 15 mg may be a feasible and clinically acceptable therapy even in very elderly patients with severe renal dysfunction, under appropriate measures for preventing bleeding.In addition to the study limitations described in our previous report,1 the sample size of this subanalysis was small, our findings are limited to very elderly patients, and the event rates were low, which may result in indeterminate conclusions. Further studies are warranted.In conclusion, the efficacy and safety of edoxaban 15 mg compared with placebo was broadly consistent across renal function subgroups in very elderly Japanese patients with NVAF who were not appropriate candidates for standard doses of oral anticoagulants.Article InformationRegistration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02801669.AcknowledgmentsWe thank Michelle Belanger, MD, of Edanz (www.edanz.com) for providing medical writing support, which was funded by Daiichi Sankyo Co., Ltd. All authors meet the ICMJE’s authorship criteria.Sources of FundingThis study was supported by Daiichi Sankyo Co., Ltd.Nonstandard Abbreviations and AcronymsCrClcreatinine clearanceNVAFnonvalvular atrial fibrillationDisclosures Dr Yoshida has received funding for research expenses (Onga Hospital) from Daiichi Sankyo Co., Ltd. Dr Shimizu has received grants from Daiichi Sankyo Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd.; and honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Daiichi Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Bristol-Meyers Squibb, K.K., Bayer Yakuhin, Ltd., Pfizer Japan, Inc., Ono Pharmaceutical Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. M. Fukuzawa, S. Watanabe, and T. Hayashi are employees at Daiichi Sankyo Co., Ltd. Dr Yamashita has received personal fees (as a medical expert) from Daiichi Sankyo Co., Ltd. for this study; and grants and lecture fees from Daiichi Sankyo Co., Ltd., Bristol-Myers Squibb K.K., and Bayer Yakuhin Ltd.; lectures fees from Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., and Ono Pharmaceutical Co., Ltd.; medical advisory fees from Toa Eiyo Ltd.; and lecture and medical advisory fees from Novartis Pharma K.K. outside the submitted work. Dr Okumura has received grants and a commission fee for the study design from Daiichi Sankyo Co., Ltd. for the submitted work; and lecture fees from Daiichi Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Bristol-Myers Squibb K.K., Medtronic Japan Co., Ltd., Johnson & Johnson K.K., and Bayer Yakuhin Ltd. outside the submitted work. Dr Akao has received funding support for the present manuscript from Daiichi Sankyo Co., Ltd. and grants from Bayer Yakuhin, Ltd., Pfizer Japan, Inc., Bristol-Meyers Squibb, K.K., Nippon Boehringer Ingelheim Co., Bayer Yakuhin, Ltd., and Daiichi Sankyo Co., Ltd. The other authors report no conflicts.FootnotesCirculation is available at www.ahajournals.org/journal/circFor Sources of Funding and Disclosures, see page 720.Correspondence to Tetsuro Yoshida, MD, PhD, Department of Cardiovascular Medicine, Onga Nakama Medical Association Onga Hospital, 1725-2 Ooaza-Ozaki, Onga-cho, Onga-gun, Fukuoka 811-4342, Japan. Email [email protected]comReferences1. Okumura K, Akao M, Yoshida T, Kawata M, Okazaki O, Akashi S, Eshima K, Tanizawa K, Fukuzawa M, Hayashi T, et al.; ELDERCARE-AF Committees and Investigators. Low-dose edoxaban in very elderly patients with atrial fibrillation.N Engl J Med. 2020; 383:1735–1745. doi: 10.1056/NEJMoa2012883CrossrefMedlineGoogle Scholar2. Bohula EA, Giugliano RP, Ruff CT, Kuder JF, Murphy SA, Antman EM, Braunwald E. Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 Trial.Circulation. 2016; 134:24–36. doi: 10.1161/CIRCULATIONAHA.116.022361LinkGoogle Scholar3. Koretsune Y, Yamashita T, Kimura T, Fukuzawa M, Abe K, Yasaka M. Short-term safety and plasma concentrations of edoxaban in Japanese patients with non-valvular atrial fibrillation and severe renal impairment.Circ J. 2015; 79:1486–1495. doi: 10.1253/circj.CJ-14-0942CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails March 1, 2022Vol 145, Issue 9Article InformationMetrics © 2022 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.https://doi.org/10.1161/CIRCULATIONAHA.121.057190PMID: 35226559 Originally publishedFebruary 28, 2022 Keywordsanticoagulantsagedthromboembolismedoxabankidneyhemorrhageatrial fibrillationPDF download Advertisement SubjectsAtrial FibrillationHeart Failure

A 79‐year‐old male with bronchiectasis was referred to our clinic because of mild chest tightness on exertion. He had no history of hemoptysis. An electrocardiogram showed ST segment depression in leads V5‐6. Multi‐detector contrast‐enhanced computed tomography revealed no significant stenosis in either coronary artery; however, a huge racemose hemangioma of the bronchial artery (RHBA) was detected. In addition, arterial supply to the RHBA via the right coronary artery (RCA) and the left internal thoracic artery (LITA) was suspected. Adenosine‐loading myocardial scintigraphy images revealed segmental hypo‐perfusion in the left ventricular inferior wall. Selective bronchial artery angiography revealed the huge RHBA. In addition, both the RCA and LITA provided arterial supply to the RHBA. To the best of our knowledge, this case is the first to show multiple arterial supply resulting in a huge RHBA.

Abstract Aims Hypertension is a strong risk factor for heart failure with preserved ejection fraction. Curcumin has p300-specific histone acetyltransferase inhibitory activity, suppresses cardiomyocyte hypertrophy and fibrosis, and significantly reduces myocardial brain natriuretic peptide (BNP) expression without altering blood pressure in a rat model of hypertensive heart disease. This double-blind, placebo-controlled, randomized study, for the first time, aimed to examine the efficacy of a high-absorption curcumin for the prevention of hypertensive heart disease in humans. Methods and results Patients exhibiting initial signs of hypertensive heart disease with left ventricular ejection fraction ≥60% and stable blood pressure <140/90 mmHg orally took a double-blinded capsule (either a 90 mg curcumin capsule or placebo) twice daily for 24 weeks. The primary endpoint was per cent changes in left ventricular diastolic function (E/E′) from baseline to 6 months after administration. The secondary endpoint was the per cent change in plasma BNP levels. The E/E′ ratio per cent change from baseline to 6 months after administration was similar between the placebo (n = 69) and the curcumin (n = 73) groups. The per cent change in plasma BNP levels was significantly lower in the curcumin group than in the placebo group. In patients <65 years, BNP per cent changes were significantly lower in the curcumin group than in the placebo group, but similar between groups in ≥65 years (<65 vs. ≥65 years: P for interaction = 0.011). Conclusions A high-absorption curcumin agent did not affect the E/E′ ratio, rather it significantly inhibited the increase in plasma BNP levels in patients with initial signs of hypertensive heart disease.

Background: Whether diabetes mellitus (DM) modifies the relationship between soluble fms-like tyrosine kinase-1 (sFlt-1), a vascular endothelial growth factor (VEGF) antagonist, and cardiovascular (CV) events in patients with suspected or known coronary artery disease (CAD) are unclear. Methods: Using data from a multicenter, prospective cohort of 3255 patients with suspected or known CAD undergoing elective coronary angiography, we assessed the impact of DM on the prognostic values of sFlt-1 and other biomarkers. Heparin-free fasting serum levels of sFlt-1, VEGF, placental growth factor, cystatin C, N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin-I (hs-cTnI), and high-sensitivity C-reactive protein (hs-CRP) were measured in 1281 DM and 1974 non-DM patients enrolled in the EXCEED-J study. The primary outcome was 3-point major adverse CV events (3P-MACE) defined as a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcomes were all-cause death, CV death, and 5P-MACE defined as a composite of 3P-MACE, heart failure hospitalization, and coronary/peripheral artery revascularization. Results: After adjusting for potential clinical confounders, serum levels of sFlt-1, NT-proBNP, hs-cTnI and cystatin C, but not other biomarkers, were significantly associated with 3P-MACE in the entire cohort. These associations were still significant for sFlt-1, NT-proBNP, and hs-cTnI, but not for cystatin C, in non-DM patients. In contrast, NT-proBNP, hs-cTnI and cystatin C, but not sFlt-1, were significantly associated with 3P-MACE in DM patients. The sFlt-1 level was also significantly associated with all-cause death and CV death in the entire cohort and in non-DM patients, but not in DM patients. It was not significantly associated with 5P-MACE in the entire cohort, non-DM patients, or DM patients. Furthermore, sFlt-1 provided an incremental prognostic information for 3P-MACE and CV death to the model with potential clinical confounders in non-DM patients, but not in DM patients. Conclusions: Serum levels of sFlt-1 were independently associated with 3P-MACE and CV death in patients with suspected or known CAD. These associations were attenuated in DM patients.

Abstract Aims Endothelial cell vascular endothelial growth factor receptor 2 (VEGFR‐2) plays a pivotal role in angiogenesis, which induces physiological cardiomyocyte hypertrophy via paracrine signalling between endothelial cells and cardiomyocytes. We investigated whether a decrease in circulating soluble VEGFR‐2 (sVEGFR‐2) levels is associated with poor prognosis in patients with chronic heart failure (HF). Methods and results We performed a multicentre prospective cohort study of 1024 consecutive patients with HF, who were admitted to hospitals due to acute decompensated HF and were stabilized after initial management. Serum levels of sVEGFR‐2 were measured at discharge. Patients were followed up over 2 years. The outcomes were cardiovascular death, all‐cause death, major adverse cardiovascular events (MACE) defined as a composite of cardiovascular death and HF hospitalization, and HF hospitalization. The mean age of the patients was 75.5 (standard deviation, 12.6) years, and 57% were male. Patients with lower sVEGFR‐2 levels were older and more likely to be female, and had greater proportions of atrial fibrillation and anaemia, and lower proportions of diabetes, dyslipidaemia, and HF with reduced ejection fraction (<40%). During the follow‐up, 113 cardiovascular deaths, 211 all‐cause deaths, 350 MACE, and 309 HF hospitalizations occurred. After adjustment for potential clinical confounders and established biomarkers [N‐terminal B‐type natriuretic peptide (NT‐proBNP), high‐sensitivity cardiac troponin I, and high‐sensitivity C‐reactive protein], a low sVEGFR‐2 level below the 25th percentile was significantly associated with cardiovascular death [hazard ratio (HR), 1.79; 95% confidence interval (CI), 1.16–2.74] and all‐cause death (HR, 1.43; 95% CI, 1.04–1.94), but not with MACE (HR, 1.11; 95% CI, 0.86–1.43) or HF hospitalization (HR, 1.03; 95% CI, 0.78–1.35). The stratified analyses revealed that a low sVEGFR‐2 level below the 25th percentile was significantly associated with cardiovascular death (HR, 1.76; 95% CI, 1.07–2.85) and all‐cause death (HR, 1.49; 95% CI, 1.03–2.15) in the high‐NT‐proBNP group (above the median), but not in the low‐NT‐proBNP group. Notably, the patients with high‐NT‐proBNP and low‐sVEGFR‐2 (below the 25th percentile) had a 2.96‐fold higher risk (95% CI, 1.56–5.85) for cardiovascular death and a 2.40‐fold higher risk (95% CI, 1.52–3.83) for all‐cause death compared with those with low‐NT‐proBNP and high‐sVEGFR‐2. Conclusions A low sVEGFR‐2 value was independently associated with cardiovascular death and all‐cause death in patients with chronic HF. These associations were pronounced in those with high NT‐proBNP levels.

Background: Smoking is a risk factor for mortality in the general population and in patients with coronary artery disease (CAD). Vascular endothelial growth factor D (VEGF-D) is a secreted glycoprotein that can act as lymphangiogenic and angiogenic growth factors. Recently, we demonstrated that circulating VEGF-D levels are associated with the risk of mortality in patients with suspected or known CAD. However, whether VEGF-D levels differ according to smoking status and whether smoking modifies the relationship between VEGF-D and mortality in those patients are unknown. Methods: Using data from a multicenter, prospective cohort of 2418 patients with suspected or known CAD, we assessed the association between smoking status and VEGF-D and the impact of smoking status on the association between VEGF-D levels and the risk of all-cause death. VEGF-D was measured in 955 never smokers, 1035 former smokers, and 428 current smokers enrolled in the ANOX Study. Patients were followed up over 3 years. Results: The mean age (standard deviation [SD]) of the patients was 70.6 (10.4) years; 67.2% were men. Current smokers exhibited significantly higher levels of VEGF-D compared to former smokers and never smokers (median [interquartile range], 343 [214-556], 312 [201-500], 291 [182-485] pg/mL, respectively; P =0.006). Stepwise multiple linear regression analysis revealed that the log-transformed VEGF-D level was independently associated with current smoking ( P =0.002), but not with former smoking. After adjusting for potential clinical confounders, the VEGF-D level was significantly associated with all-cause death in never smokers (hazard ratio per 1-SD increase [HR], 1.31; 95% confidence interval [CI], 1.10-1.55) and in former smokers (HR, 1.22; 95% CI, 1.08-1.37), but not in current smokers (HR, 0.92; 95% CI, 0.65-1.22). Furthermore, VEGF-D provided incremental prognostic information to the model with potential clinical confounders and the established cardiovascular biomarkers in never smokers, but not in former smokers or in current smokers. Conclusions: Current smoking was independently associated with higher levels of VEGF-D. The prognostic value of VEGF-D on mortality was most pronounced in never smokers among patients with suspected or known CAD.

Introduction: Soluble vascular endothelial growth factor receptor-2 (sVEGFR-2) acts as an endogenous inhibitor of VEGF, a key regulator of angiogenesis and lymphoangiogenesis. However, little is known about the critical role of sVEGFR-2 in heart failure (HF). Methods: We performed a multicenter prospective cohort study (PREHOSP-CHF Study) to determine the predictive value of sVEGFR-2 for major adverse cardiovascular (CV) events (MACE) among patients with chronic HF (CHF). A total of 1,021 patients were included in the analyses. The mean age (SD) was 75.5 (12.6) years. 59.6% were male. The primary outcome was MACE defined as a composite of CV death or HF hospitalization. The secondary outcomes were all-cause death and CV death. Serum levels of sVEGFR-2 were determined employing specific enzyme-linked immunosorbent assays. Results: The patients with lower sVEGFR-2 concentrations were older, and had higher rates of female sex, atrial fibrillation and anemia. The baseline sVEGFR-2 level was inversely correlated with left ventricular ejection fraction, and was positively correlated with the body mass index. During the median follow-up of 730 days, a total of 210 (20.6%) all-cause deaths, 99 (9.7%) CV deaths and 308 (30.2%) HF hospitalizations occurred. Unadjusted Cox proportional hazard analyses revealed that the patients with the lowest quartile (Q1) of sVEGFR-2 did not show a significantly higher risk of MACE (p=0.7), but showed the greatest risks of CV death (p=0.003) and all-cause death (p=0.007). Even after adjusting for established risk factors and CV biomarkers (N-terminal pro-brain natriuretic peptide, contemporary sensitive cardiac troponin-I, and high-sensitivity C-reactive protein), those with the Q1 of sVEGFR-2 exhibited the greatest risk of CV death (p=0.02; hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.17-3.66 [vs. Q2]; HR, 2.42; 95%CI, 1.30-4.68 [vs. Q3]; HR, 1.52; 95%CI, 0.80-2.99 [vs. Q4]), but not that of all-cause death. The sex-stratified analyses revealed that the association between sVEGFR-2 and CV death was still significant in men, but not in women (p for interaction, 0.07). Conclusions: A low sVEGFR-2 value was not associated with MACE, but was independently associated with CV mortality among patients with CHF.

Background: High circulating levels of galectin-3 are associated with all-cause mortality, cardiovascular (CV) mortality, and/or major adverse CV events (MACE) in patients with CV diseases such as heart failure and coronary artery disease (CAD). However, the impact of sex on the prognostic value of galectin-3 in patients with suspected or known CAD remains unclear. Methods: Using data from a multicenter, prospective cohort of 2418 patients with suspected or known CAD, we assessed the impact of sex on the association between galectin-3 levels and the risks of all-cause death, CV death, and MACE defined as a composite of CV death, nonfetal myocardial infarction, and nonfetal stroke. Galectin-3 was measured in 1624 men and 794 women enrolled in the ANOX Study. Patients were followed up over 3 years. Results: The mean ages (standard deviations) were 69.8 (10.6) years in men and 72.2 (9.9) years in women ( P <0.001). Men exhibited significantly lower levels of galectin-3 compared to women (median [interquartile range], 9.0 [6.9-11.9] versus 9.6 [7.3-12.4] ng/mL, respectively; P =0.004). In the entire patient cohort, the galectin-3 level was significantly associated with all-cause death (hazard ratio per 1 standard deviation increase [HR], 1.28; 95% confidence interval [CI], 1.16-1.42), CV death (HR, 1.24; 95% CI, 1.04-1.46), and MACE (HR, 1.24; 95% CI, 1.09-1.41) after adjusting for potential clinical confounders. These associations were still significant in women (HR for all-cause death, 1.59; 95% CI, 1.26-1.98; HR for CV death, 1.53; 95% CI, 1.06-2.21; HR for MACE, 1.61; 95% CI, 1.21-2.09), whereas in men, galectin-3 was significantly associated with all-cause death (HR, 1.23; 95% CI, 1.08-1.39), but not with CV death (HR, 1.14; 95% CI, 0.93-1.40) or MACE (HR, 1.15; 95% CI, 0.99-1.35). Furthermore, galectin-3 provided incremental prognostic information for all-cause death, but not for CV death or MACE, to the model with potential clinical confounders and the established CV biomarkers in the entire cohort and in women, but not in men. Conclusions: We identified a significantly stronger prognostic value of galectin-3 in women than in men among patients with suspected or known CAD.

Background The lymphatic system has been suggested to play an important role in cholesterol metabolism and cardiovascular (CV) disease. Recently, we demonstrated that serum levels of vascular endothelial growth factor C (VEGF-C), a central player of lymphangiogenesis, are inversely and independently associated with the risk of all-cause mortality in patients with suspected or known coronary artery disease (CAD). However, the impact of anemia on the relationship between VEGF-C and mortality in those patients is unclear. Methods Serum VEGF-C levels were measured in 2,418 patients with suspected or known CAD undergoing elective coronary angiography, enrolled in the development of novel biomarkers related to angiogenesis or oxidative stress to predict CV events (ANOX) study, and followed up for 3 years. Anemia was defined as a hemoglobin level of less than 13 g/dL in men and <12 g/dL in women. Patients were divided into 2 groups according to the presence (anemic, n=882) or absence (non-anemic, n=1,536) of anemia. The primary outcome was all-cause death. The secondary outcomes were CV death, and major adverse CV events (MACE) defined as a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. Results During the follow-up, 164 anemic and 90 non-anemic patients died from any cause, 64 anemic and 24 non-anemic patients died from CV disease, and 96 anemic and 69 non-anemic patients developed MACE. After adjustment for established risk factors, VEGF-C levels were significantly and inversely associated with all-cause death (hazard ratio [HR] for 1-SD increase, 0.71; 95% confidence interval [CI], 0.59–0.84), CV death (HR, 0.60; 95% CI, 0.44–0.79), and MACE (HR, 0.76; 95% CI, 0.60–0.95) in anemic, while VEGF-C levels were not significantly associated with all-cause death (HR, 0.87; 95% CI, 0.69–1.11), CV death (HR, 1.32; 95% CI, 0.85–1.93), or MACE (HR, 1.12; 95% CI, 0.87–1.42) in non-anemic patients. Even after incorporation of N-terminal pro-brain natriuretic peptide, contemporary sensitive cardiac troponin I, and high-sensitivity C-reactive protein into a model with established risk factors, the addition of VEGF-C levels further improved the prediction of all-cause death (P<0.001 for continuous net reclassification improvement [NRI], P=0.006 for integrated discrimination improvement [IDI]) and CV death (P<0.001 for NRI, P=0.005 for IDI), but not that of MACE (P=0.021 for NRI, P=0.059 for IDI) in anemic, whereas the addition of VEGF-C levels did not improved the prediction of all-cause death (P=0.234 for NRI, P=0.415 for IDI), CV death (P=0.190 for NRI, P=0.392 for IDI) or MACE (P=0.897 for NRI, P=0.128 for IDI) in non-anemic patients. Conclusions The VEGF-C level was inversely and independently associated with all-cause and CV mortality in anemic, but not in non-anemic patients with suspected or known CAD. The inverse relationship between VEGF-C and mortality may depend on the presence of anemia. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): The ANOX study is supported by a Grant-in-Aid for Clinical Research from the National Hospital Organization.

Metformin is the most widely used oral antihyperglycemic agent for patients with type 2 diabetes mellitus (T2DM). Despite the possible benefits of metformin on diabetes mellitus (DM) and heart failure (HF), acute or unstable HF remains a precaution for its use. The aim of the present prospective randomized controlled trial was to assess whether metformin treatment has beneficial effects on patients with T2DM with hypertension without overt HF. A total of 164 patients (92 males, 72 females; median age 66 years) were included in this study. Patients with T2DM with a history of hypertension were randomized 1:1 to treatment for 1 year with either metformin (metformin-treated group) or other hypoglycemic agents (control group). The primary endpoints were changes in brain natriuretic peptide (BNP) levels, left ventricular (LV) mass index, and indicators of LV diastolic function. We also evaluated changes in both clinical findings and blood laboratory examination data. We observed no significant changes between baseline and 1-year post-treatment in LV mass index, BNP levels, or E/e′ (early diastolic transmitral flow velocity/early diastolic mitral annular velocity; an indicator of LV diastolic function) in either the metformin-treated (n = 83) or the control (n = 81) groups. The metformin-treated group had a significant reduction of body mass index (BMI) and low-density lipoprotein cholesterol (LDL-C), but the control group did not. We determined that renal function, including serum creatinine and estimated glomerular filtration rate, deteriorated significantly in the control group but not in the metformin-treated group. LV mass and diastolic function were not affected after 1 year of metformin treatment in patients with T2DM. However, we observed benefits in terms of reductions in both BMI and LDL-C levels and preservation of renal function. UMIN000006504. Registered 7 October 2011.

Objective To establish a simple screening method for diabetes based on myoinositol (MI) in urine samples collected at home. Research design and methods Initially, we evaluated the stability of urinary MI (UMI) at room temperature (RT; 25°C) and 37°C in 10 outpatients with type 2 diabetes. We then enrolled 115 volunteers without a current or history of diabetes. In all subjects, glucose intolerance was diagnosed by 75 g oral glucose tolerance test (75gOGTT). To assess the association between UMI or urine glucose (UG) and plasma glucose (PG), urine samples were also collected at 0 and 2 hours during 75gOGTT. All the subjects collected urine samples at home before and 2 hours after consuming the commercially available test meal. UMI levels at wake-up time (UMI wake-up ), before (UMI premeal ) and 2 hours after the test meal (UMI 2h-postprandial ) were measured using an enzymatic method. ΔUMI was defined as UMI 2h-postprandial minus UMI premeal . Results Differing from UG, UMI was stable at RT and 37°C. UMI was increased linearly along with an increase in PG, and no threshold for UMI was observed. UMI was closely associated with blood glucose parameters obtained from a 75gOGTT and hemoglobin A1c (HbA1c) at hospital after adjustment for age, sex, body mass index and serum creatinine. UMI wake-up , UMI premeal , UMI 2h-postprandial and ΔUMI at home were higher in diabetic subjects than non-diabetic subjects even after the above adjustment. Receiver operating characteristics curve (ROC) analyses revealed that for the screening of diabetes, the area under the curve for ROC for UMI 2h-postprandial and ΔUMI (0.83 and 0.82, respectively) were not inferior to that for HbA1c ≥48 mmol/mol, which is the American Diabetes Association (ADA) criteria for diabetes. Conclusions MI measurement in urine samples collected at home before and after the meal would be a simple, non-invasive and valuable screening method for diabetes.