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ObjectivesNatriuretic peptides are an important prognostic marker in patients with heart failure (HF). However, little is known regarding their prognostic significance in patients with atrial fibrillation (AF) without HF and natriuretic peptides levels are underused in these patients in daily practice.MethodsThe Fushimi AF Registry is a community-based prospective survey of patients with AF in Fushimi-ku, Kyoto, Japan. We investigated patients with AF without HF (defined as prior HF hospitalisation, New York Heart Association functional class≥2 or left ventricular ejection fractionResultsOf 1159 patients (mean age: 72.1±10.2 years, median CHA2DS2-VASc score: 3 and oral anticoagulant (OAC) prescription: 671 (56%)), the median NT-proBNP level was 488 (IQR 169–1015) ng/L. Patients with high NT-proBNP levels were older, had higher CHA2DS2-VASc scores and had more OAC prescription (all pConclusionNT-proBNP levels are a significant prognostic marker for adverse outcomes in patients with AF without HF and may have clinical value.Trial registration numberUMIN000005834.

Data regarding the associations of anemia (hemoglobin level

Objective The psychological status is a key factor in smoking continuance. However, details on short-term changes in mild depressive states after smoking cessation (SC) are still unknown. The purpose of the present study was to investigate these short-term changes. Methods A total of 989 patients who visited our SC Clinic were assessed using the Zung Self-Rating-Depression-Scale (SDS), an official instrument to measure depressive tendencies. The participants were classified into normal and neurotic groups based on their SDS scores during their initial visit; they were assessed again 2, 4, 8, and 12 weeks thereafter. Results The majority of patients in the neurotic group were women. These patients were also younger, with a higher nicotine dependence, and presented with a lower successful SC rate than the patients in the normal group. A decrease in SDS scores after starting the SC treatment was observed only in the neurotic group, especially during the first two weeks. In patients who continued to smoke, no improvement in depressive tendencies was noted in this period. Conclusion Depressive tendencies of patients with neurosis improve in the initial stages of the SC treatment (i.e., within two weeks after starting the treatment). This finding fills the mentioned knowledge gap regarding the effects of SC on mild depressive states in the short term.

Pathological stresses such as pressure overload and myocardial infarction induce cardiac hypertrophy, which increases the risk of heart failure. Cacao bean polyphenols have recently gained considerable attention for their beneficial effects on cardiovascular diseases. This study investigated the effect of cacao bean polyphenols on the development of cardiac hypertrophy and heart failure. Cardiomyocytes from neonatal rats were pre-treated with cacao bean polyphenols and then stimulated with 30 µM phenylephrine. C57BL/6j male mice were subjected to sham or transverse aortic constriction surgery and then orally administered with vehicle or cacao bean polyphenols. Cardiac hypertrophy and function were examined by echocardiography. In cardiomyocytes, cacao bean polyphenols significantly suppressed phenylephrine-induced cardiomyocyte hypertrophy and hypertrophic gene transcription. Extracellular signal-regulated kinase 1/2 and GATA binding protein 4 phosphorylation induced by phenylephrine was inhibited by cacao bean polyphenols treatment in the cardiomyocytes. Cacao bean polyphenols treatment at 1200 mg/kg significantly ameliorated left ventricular posterior wall thickness, fractional shortening, hypertrophic gene transcription, cardiac hypertrophy, cardiac fibrosis, and extracellular signal-regulated kinase 1/2 phosphorylation induced by pressure overload. In conclusion, these findings suggest that cacao bean polyphenols prevent pressure overload-induced cardiac hypertrophy and systolic dysfunction by inhibiting the extracellular signal-regulated kinase 1/2-GATA binding protein 4 pathway in cardiomyocytes. Thus, cacao bean polyphenols may be useful for heart failure therapy in humans.

Background Antithrombotic therapies that are optimal for atrial fibrillation (AF) patients undergoing percutaneous coronary intervention (PCI) have been studied but remain uncertain. We often encounter difficulties in choosing an appropriate antithrombotic therapy with antiplatelet agents after PCI in AF patients treated with oral anticoagulant due to a high CHADS2 score. Since there are no data on the incidences of PCI procedures in AF patients, we evaluated those incidences as well as the association between PCI and the CHADS2 score using data from the Fushimi AF Registry. Methods The Fushimi AF Registry is a community-based prospective cohort study of AF patients in Fushimi-ku, Kyoto, Japan. Follow-up data were available for 4325 patients, and the median follow-up was 3.6 (interquartile range: 1.9–5.9) years. Results There were 143 PCI procedures performed in 122 patients during follow-up, and 28 (20%) were emergent ones. The crude incidence of PCI procedures was 9.36 per 1000 person-years. At 1 and 3 years, the cumulative incidences of PCI were 46 (1.1%) and 85 (2.4%), respectively. As for 4 age groups: Conclusions About 1 in 100 AF patients underwent PCI annually, and patients with a CHADS2 score ≥2 were associated with higher incidences of PCI procedures.

Background There is a growing burden of valvular heart disease (VHD) and atrial fibrillation (AF) due to population aging, but data regarding the characteristics and outcomes of patients with AF and concomitant VHD are lacking.Methods and Results:The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto. Among 3,566 patients with available echocardiographic data, 20% had VHD, consisting of 131 valvular AF (VAF: 3.7%) and 583 nonvalvular AF with VHD (NVAF-VHD: 16.3%). Here, VAF was defined as AF with mitral stenosis or a prosthetic heart valve. AF patients with VHD were older, had more comorbidities with a higher CHADS2 score, and were prescribed oral anticoagulants more frequently than those without VHD. After adjusting for confounders, VHD was not associated with stroke or systemic embolism, all-cause mortality, or cardiac death. NVAF-VHD was significantly associated with an increased risk of hospitalization for heart failure (adjusted hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.16-1.78), whereas VAF was not (HR, 1.28; 95% CI, 0.86-1.92). Among all types of VHD, aortic valve diseases were associated with a higher risk of cardiac events, whereas mitral valve diseases were not. Conclusions Although VHD did not significantly affect thromboembolism or mortality, it affected cardiac events depending on type, with aortic valve diseases having higher risk, in Japanese patients with AF.

Background: Smoking exerts detrimental effects during the progression of atherosclerotic vascular disease. Serum cystatin C is useful in the evaluation of early renal dysfunction and serves as a cardiovascular prognostic marker. This study measured changes in serum cystatin C after smoking cessation (SC). Methods and Results: In this study, patients who visited the SC clinic for the first time and succeeded in SC for 1 year were enrolled. In the entire cohort of 86 patients, body mass index (BMI, P

Background: We previously reported that left atrial enlargement (LAE) was an independent predictor of stroke/systemic embolism (SE) in Japanese atrial fibrillation (AF) patients. Mitral regurgitation (MR) likely accompanies LAE; it sometimes causes LAE and conversely LAE can cause secondary MR. However, the relationship between MR and LAE on the risk of stroke/SE is unknown. Purpose: The aim of this study is to investigate the impact of LAE on stroke/SE in AF patients with or without MR. Method: The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto, which is a typical urban district of Japan. We started to enroll patients from March 2011, and follow-up data were available for 4,472 patients by the end of October 2020. In the entire cohort, echocardiography data were available for 3,622 patients. 131 AF patients with rheumatic mitral stenosis or prosthetic valve and 63 patients without data of left atrial diameter (LAD) were excluded. We divided eligible 3,428 patients in MR group (n=393) and non-MR group (n=3,035). We compared clinical characteristics and rates of stroke/SE between patients with LAE (LAD > 45mm) and without LAE (Non-LAE) in each group. Result: In both MR and non-MR groups, patients with LAE were, as compared with non-LAE, more in body weight, more often persistent/permanent type, more likely to have chronic kidney disease. LAE group was older, more likely have heart failure, hypertension, diabetes mellitus and more often received oral anticoagulant in non-MR group, but not in MR group. During the median follow-up of 1,804 days, the incidence rate of stroke/SE was higher in LAE than non-LAE in non-MR group (2.13 vs. 1.08 per 100 person-years, respectively, log rank p Conclusion: The incidence rate of stroke/SE was higher in LAE than non-LAE in non-MR group, but not in MR group.

Background: Atrial fibrillation (AF) is associated with an increased risk of cardioembolic stroke and systemic embolism (SE). A secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that low diastolic blood pressure (DBP) was not related to risk of the first episode of stroke in hypertensive patients who received prescription of any antihypertensive agents. However, data regarding the impact of low on-treatment DBP on the first episode of stroke or SE in AF patients are limited. Methods: The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto, Japan. Follow-up data were available in 4,472 patients, and hypertensive patients who received prescription of any antihypertensive agents, and without prior stroke or SE were examined (n=1,934).We divided these patients into four groups based on the quartile of DBP; Q1 (DBP< 63 mmHg, n=463), Q2 (63 mmHg≤DBP Results: Patients in Q1 group were older (Q1 vs. Q2 vs. Q3 vs. Q4; 77.2±0.45 vs. 74.2±0.45 vs. 73.6±0.44 vs. 71.0±0.42; p Conclusion: In Japanese AF patients without prior stroke or SE, low on-treatment DBP was associated with the incidence of stroke or SE.

Background: The ELDERCARE-AF trial demonstrated that low-dose edoxaban (15 mg once-daily) prevented stroke or systemic embolism (SE) in very elderly Japanese patients with nonvalvular atrial fibrillation (NVAF) who were inappropriate for standard oral anticoagulant therapy due to high bleeding risk. The association between clinical outcomes and bleeding risks in such patients in routine clinical practice are unclear. Methods: From the Fushimi AF registry, we obtained ELDERCARE-eligible patients with NVAF who aged ≥80 years, had CHADS 2 score ≥2, and had one or more bleeding risks as shown in the ELDERCARE-AF trial: low creatinine clearance (15 to 30 ml/min), a history of bleeding from a critical organ, low body weight (≤45 kg), or regular use of antiplatelet drugs. The association of the four bleeding risk factors with the outcomes was evaluated in eligible patients. Results: We obtained 549 ELDERCARE-eligible patients (12.8% of entire cohort, 52.8% of ≥80 years and CHADS 2 score ≥2). The median follow-up period was 1,823 (interquartile range: 809-2,900) days. The incidences (% per patient-year) of stroke/SE, major bleeding, all-cause mortality, and cardiovascular death were significantly higher in eligible patients than in non-eligible patients (stroke/SE: 4.6% vs. 2.0%, major bleeding: 3.5% vs. 1.8%, all-cause mortality: 15.5% vs. 3.9%, cardiovascular death: 2.9% vs. 0.6%, all log-rank P Conclusion: Patients with NVAF who met the inclusion criteria of the ELDERCARE-AF trial had poor clinical outcomes, and low creatinine clearance was associated with the incidences of both all-cause and cardiovascular mortality.

Background: Frailty is a complex clinical syndrome associated with ageing and chronic illness, and is common in heart failure (HF). Vascular endothelial dysfunction including maladaptive angiogenesis and lymphangiogenesis is involved in the pathogenesis of HF, and is also considered to be the causes of frailty. We investigated the association of vascular endothelial growth factor (VEGF) families, central regulators of angiogenesis and lymphangiogenesis, with frailty, and prognostic role of these cytokines in frail HF patients. Methods: We performed a multicenter prospective cohort study to determine the predictive value of VEGF families for prognosis 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 VEGF, VEGF-C, VEGF-D, and soluble VEGF receptor-2 (sVEGFR-2) were measured. Frailty was assessed by Canadian Study of Health and Aging Clinical Frailty Scale (CFS). Results: A total of 256 (25.1%) patients had frailty (CFS≥5) at baseline. Frail patients were older, more likely female, and had lower body mass index, higher NYHA class, and higher rates of prior hospitalization for HF, HF with preserved ejection fraction, anemia, cerebrovascular disease, and dementia. N-terminal pro brain natriuretic peptide, high sensitivity troponin I, and high sensitivity C-reactive protein levels were higher in frail patients. During the 2-year follow-up, 211 all cause death occurred. In Kaplan-Maier analysis, frail patients showed significantly higher incidence of all-cause (hazard ratio [HR], 4.12; 95% confidence interval [CI], 3.14-5.42). Regarding VEGF families, frail patients had significantly lower levels of sVEGFR-2 and VEGF-C, and higher levels of VEGF-D. Multiple regression analysis revealed that VEGF-C had inverse correlation with CFS (P, 0.03). After adjusting for clinical confounders, a low VEGF-C level was independently associated with all-cause death in frail patients (HR, 0.74; 95%CI, 0.58-0.94 for 1-SD increase), but was not in non-frail patients (HR, 0.87; 95%CI, 0.64-1.14 for 1-SD increase) (P for interaction, 0.09). Conclusions: In HF patients, a low VEGF-C value was associated with frailty and was independent risk for all-cause death in frail patients.

Background Hypertension is one of the major risk factors of cardiovascular events in patients with atrial fibrillation (AF). Low diastolic blood pressure (DBP) has been reported to be associated with the incidence of cardiovascular events, but current guidelines recommend an intensive blood pressure target of less than 130/80 mmHg for AF patients taking oral anticoagulants without mentioning the lower limits of DBP. Methods The Fushimi AF Registry is a community-based prospective survey of AF patients in a city of Japan. Follow-up data were available in 4,472 patients, and hypertensive patients who received prescription of any antihypertensive agents and whose systolic blood pressure was treated to less than 130 mmHg were available were examined (n=1,319). We divided the patients into four groups according to their DBP at baseline; G1 (DBP Results The proportion of female was grater in G1 group, and the patients in G1 group were older. During the median follow-up of 2,458 days, in Kaplan-Meier analysis, the incidence rates of cardiovascular events (composite of cardiac death, ischemic stroke, systemic embolism, non-fatal myocardial infarction and heart failure hospitalization during follow up) were the highest in G1 group and the lowest in G3 group (G1: 7.2% per person-year vs. G2: 4.9% vs. G3: 2.2% vs. G4: 4.4%; p Conclusion In Japanese AF patients whose systolic blood pressure was treated to less than 130 mmHg, patients with excessively low DBP had significantly higher incidence of cardiovascular events, and DBP exhibited J curve association with higher incidence of cardiovascular events. Funding Acknowledgement Type of funding sources: None.

Background Thrombocytopenia is sometimes found in routine blood tests and is associated with an increased risk of mortality in general population. We have previously reported that atrial fibrillation (AF) patients with thrombocytopenia have a higher mortality than those without thrombocytopenia. However, association of the degree of thrombocytopenia with cause of death in AF patients is unknown. Purpose We aimed to investigate the association of baseline platelet count with cause of death including cardiac death, intracranial death, malignancy, infection, extracranial bleeding death, renal failure death, respiratory failure death and undetermined death. Methods The Fushimi AF Registry was designed to enroll all of the AF patients in Fushimi-ku, Kyoto. Fushimi-ku is densely populated with a total population of 283,000 and is assumed to represent a typical urban community in Japan. We started to enroll patients from March 2011, and follow-up data with baseline platelet counts less than 150,000/μL were available in 853 patients by the end of September 2020. We divided them into 3 groups according to baseline platelet level: Mild thrombocytopenia (100,000–149,999/μL, n=703), Moderate thrombocytopenia (50,000–99,999/μL, n=120), and Severe thrombocytopenia ( Results In the entire cohort, the mean age was 76 years, 34% were women, the mean body weight and body mass index was 59.3 kg and 22.9 kg/m2, and the median platelet count were 121,000/μL (interquartile range 109,000 to 141,000/μL). Compared to Mild thrombocytopenia, patients with Moderate or Severe thrombocytopenia were more likely to have chronic kidney disease (42.2% vs 54.2% vs 73.3%, p=0.0003), have higher HAS-BLED score (1.90 vs 2.14 vs 2.00, p=0.047) and lower hemoglobin (12.8g/dL vs 11.7g/dL vs 11.2g/dL, p Conclusion Mortality was higher according to the degree of thrombocytopenia in AF patients, but the cause of death was not different among three groups. Funding Acknowledgement Type of funding sources: None.

Background Hyperlipidemia is a well-established risk factor for cardiovascular disease. However, low cholesterol is also reported to be associated with poor outcome in patients with chronic disease, which is called “cholesterol paradox”, and the association of cholesterol level with the incidence of clinical outcomes in patients with atrial fibrillation (AF) remains unclear. Methods In the Fushimi AF Registry, a community-based prospective survey of the AF patients in Fushimi-ku, Kyoto, Japan, follow-up data and baseline total cholesterol levels were available in 3,054 patients. We excluded 767 patients who were taking statins, and 2,267 patients were included in the analyses. We defined low cholesterol as total cholesterol Results Patients with low cholesterol (N=464 (20.4%)) were older, more often male, and had higher prevalence of low body weight ( Conclusion Low total cholesterol level was significantly associated with the incidence of all-cause and stroke/SE in AF patients not taking statins, suggesting the existence of cholesterol paradox in AF. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Boehringer Ingelheim, Bayer Healthcare, Pfizer, Bristol-Myers Squibb, Astellas Pharma, AstraZeneca, Daiichi-Sankyo, Novartis Pharma, MSD, Sanofi-Avent

Background The lymphatic system has been suggested to play an important role in cardiovascular (CV) diseases including heart failure (HF). Vascular endothelial growth factor C (VEGF-C) and VEGF-D are key regulators of lymphoangiogenesis. Purpose To investigate the association of VEGF-C and VEGF-D with prognosis in patients with chronic HF (CHF). Methods The PREHOSP-CHF study is a multicenter prospective cohort study to determine the predictive value of angiogenesis-related biomarkers in CHF. A total of 1,024 patients (mean age, 75.5±12.6 years; male, 58.7%) admitted to acute decompensated HF were included in the analyses. The primary outcome was MACE defined as a composite of CV death or HF hospitalization. The secondary outcomes were all-cause death, CV death, and HF hospitalizations. Serum levels of VEGF-C and VEGF-D, as well as N-terminal pro B-type natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin-I (hs-cTnI), high sensitive C reactive protein (hs-CRP), VEGF, and soluble VEGF receptor-2 (sVEGFR-2) were measured at the time of discharge. Patients were followed-up over two years. Results Median [interquartile range] of VEGF-C and VEGF-D levels were 4821 [3633–6131] pg/ml and 404 [296–559] pg/ml, respectively. In multivariate stepwise regression analysis, independent determinants of VEGF-C levels were younger age, female gender, absence of prior HF hospitalization, chronic kidney disease, and anemia, lower ejection fraction, lower NT-proBNP levels, higher VEGF levels, and higher sVEGFR-2 levels, while those of VEGF-D levels were lower body mass index, presence of diabetes and atrial fibrillation, and higher NT-proBNP levels. During the follow-up, a total of 209 (20.4%) all-cause deaths, 112 (10.9%) CV deaths, and 309 (30.2%) HF hospitalizations occurred. After adjusting for established risk factors and CV biomarkers, VEGF-C levels were significantly and inversely associated with the incidence of MACE and non-CV death (Fig.1, model 4). On the other hand, VEGF-D levels were significantly and positively associated with the incidence of HF hospitalization (Fig. 1, model 4). When we divided the patients into 4 groups based on the median of VEGF-C and VEGF-D levels, patients with low VEGF-C and high VEGF-D showed significantly higher incidence of MACE, all-cause death, CV death, and HF hospitalization compared to those with high VEGF-C and low VEGF-D (Fig. 2). Conclusions Among patients with CHF, VEGF-C and VEGF-D had different characteristic and association with the incidence of adverse events. VEGF-C levels were inversely associated with the incidence of MACE and non-CV death, and VEGF-D levels were positively associated with the incidence of HF hospitalization. These results suggests different effects of VEGF-C and VEGF-D in CHF. Combination of VEGF-C and VEGF-D enables us to make good risk stratification in patients with CHF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grant-in-Aid for Clinical Research from the National Hospital Organization Figure 1Figure 2

Background Atrial fibrillation (AF) is a common arrhythmia and a risk factor for thromboembolism including ischemic stroke (IS) and systemic embolism (SE). Thrombus formation mainly occurs in the left atrium (LA), but we reported that relative wall thickness (RWT) of left ventricle (LV) was independently associated with IS/SE among patients with non-valvular AF. Little is known about the impact of LV size on thromboembolism in patients with AF. We investigated the relationship between left ventricular end-diastolic diameter (LVDd) and incidence of IS /SE, using data from the Fushimi AF Registry. Methods The Fushimi AF Registry, a community-based prospective survey, was designed to enroll all of the AF patients in the community. Follow-up data were available for 4,472 patients as of November 2020, and the median follow-up period was 1,820 days. Of them, we excluded 226 patients with mitral stenosis or prior cardiac valve surgery. Among 4,246 non-valvular AF patients, follow-up data including LVDd at the baseline from echocardiography were available for 3,311 patients. We divided these patients into three groups according to LVDd tertile (T1: Results Percentage of female (T1 vs. T2 vs T3; 56.5 vs. 37.5 vs. 34.1%; p Conclusion LVDd was independently associated with IS/SE among Japanese patients with non-valvular AF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): the Practical Research Project for Life-Style-related Diseases including Cardiovascular Diseases and Diabetes Mellitus from Japan Agency for Medical Research and Development

Background Patients with atrial fibrillation (AF) occasionally require pacemaker implantation. Meanwhile, patients with implanted pacemaker are occasionally found to have subclinical AF and develop clinical AF. However, little is known about the clinical outcomes of AF patients with implanted pacemaker. Purpose We aimed to investigate the clinical outcomes in AF patients undergoing previous pacemaker therapy. Methods The Fushimi AF Registry is a community-based prospective survey of the AF patients in a city of Japan. Follow-up data including prescription status were available for 4,447 patients. After exclusion of patients with implantable cardioverter defibrillator and cardiac resynchronization therapy, we investigated 293 AF patients with pacemaker implantation at baseline. We performed propensity score-matching analysis to assess the impact of pacemaker therapy in AF patients. Results Of a total cohort, patients with pacemaker were more often female (51.2% vs. 39.7%; p Conclusion We identified that patients undergoing previous pacemaker therapy were not associated with the incidence of various adverse clinical events in Japanese AF patients. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boehringer Ingelheim, Bayer Healthcare, Pfizer, Bristol-Myers Squibb, Astellas Pharma, AstraZeneca, Daiichi Sankyo, Novartis Pharma, MSD, Sanofi-Aventis, Takeda Pharmaceutical, and the Practical Research Project for Life-Style related Diseases including Cardiovascular Diseases and Diabetes Mellitus from Japan Agency for Medical Research and Development.

Background Soluble fms-like tyrosine kinase-1 (sFlt-1), a vascular endothelial growth factor (VEGF) antagonist, has been suggested as a marker of endothelial dysfunction. Circulating sFlt-1 levels are associated with adverse outcomes in patients with preeclampsia, chronic kidney disease, and heart failure. Atrial fibrillation (AF) and coronary artery disease (CAD) are both associated with endothelial dysfunction. However, whether sFlt-1 can predict cardiovascular (CV) events and whether AF modifies the relationship between sFlt-1 and CV events in patients with suspected or known CAD are unknown. Methods We performed a nationwide, multicenter, prospective cohort study to determine the prognostic value of sFlt-1 and other biomarkers in patients with suspected or known CAD undergoing elective angiography. Heparin-free fasting serum was collected from the peripheral vein to determine levels of sFlt-1, VEGF, placental growth factor, cystatin C, neutrophil gelatinase-associated lipocalin, N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin-I (hs-cTnI), and high-sensitivity C-reactive protein (hs-CRP). 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 3311 patients were consecutively enrolled between Nov 2013 and May 2017. After excluding 56 ineligible patients, 3255 patients (324 AF and 2931 non-AF) were followed up over 3 years (follow-up rate, 99%). During the follow-up, 156 patients developed 3P-MACE, 215 died from any cause, 82 died from cardiovascular disease, and 1361 developed 5P-MACE. The sFlt-1 level was significantly higher in AF compared to non-AF patients (p Conclusions Serum levels of sFlt-1 were significantly associated with 3P-MACE in patients with suspected or known CAD. This association was pronounced in AF patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The EXCEED-J study is supported by Health Labour Sciences Research Grant (2013-2014), AMED (2015-2017, Grant Number JP17ek0210008) and Grant-in-Aid for Clinical Research from the National Hospital Organization (2018-2020).

Elevated neutrophil/lymphocyte ratio (NLR) has been reported as a sensitive marker for predicting poor prognosis in chronic inflammation-based diseases such as stroke, heart failure, cancers, and diabetes, as well as acute inflammatory diseases such as bacterial and viral infections, including COVID-19. NLR is also known to increase with age and is considered to be an aging marker. We conducted a double-blind, placebo-controlled trial in elderly volunteers to examine the effect of a newly developed, highly bioavailable curcumin formulation (curcuRouge

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 (

Background 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. Objective 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. Methods 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. Results 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. Conclusion 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. Trial Registration UMIN000006504. Registered 7 October 2011.

The baseline data obtained in the CKD-JAC demonstrated that insufficient treatment was being provided for renal anemia by institutions specializing in renal disease. The objective of this study was to investigate the status of treatment for renal anemia, including renal/cardiovascular outcomes and mortality, at regional medical facilities since the development of long-acting erythropoiesis-stimulating agents (LA-ESA). Non-dialysis outpatients with chronic kidney disease and renal anemia were eligible. Anemia was treated based on the clinical condition of each patient and targeted hemoglobin (Hb) levels. A total of 283 patients from 21 institutions were enrolled and followed up for a maximum of 3 years. A doubling of the serum creatinine level was observed in 89 patients, and renal replacement therapy was initiated in 57 patients. Multivariate Cox regression analysis revealed that a lower mean Hb level (mHb) and receiving fewer frequency of ESA during the follow-up period were independent determinants of the composite renal outcome and overall mortality. During the follow-up period, the percentages of patients with mHb of 10–10.9 g/dL and ≥ 11 g/dL were increased. Similar trends were seen regardless of whether the patients were treated by nephrologists or non-nephrologists. The frequency of ESA treatment was increased among the patients treated by non-nephrologists; however, it was much lower than nephrologists. This study demonstrated that, in the era of LA-ESA treatment, higher Hb levels are associated with reduced composite renal outcomes at regional medical facilities. The importance of renal anemia management should be highlighted, even among non-nephrologists.

Background: Obesity, which leads to left arterial remodeling, increases the risk for the development of atrial fibrillation (AF). We previously demonstrated the progression from paroxysmal to sustained AF was associated with an increased risk of ischemic stroke or hospitalization for heart failure (HF). However, the risk of progression from paroxysmal to sustained AF in obese patients has not been fully evaluated. Methods: Based on the initial type of AF and whether paroxysmal AF progressed to sustained AF during follow-up (FU), patients enrolled in the Fushimi AF registry were categorized into 3 groups; i) paroxysmal AF without progression, ii) paroxysmal AF with progression, iii) sustained AF. Obesity was defined as BMI at baseline >30. Results: Obese patients (172/3834) had a higher prevalence of sustained AF at baseline as compared with those without obesity (58.7% vs 51.0%, p=0.047), and they had a higher rate of progression from paroxysmal to sustained AF during a median FU of 4.3 years (2.4% vs 1.5% [per person-year], p Conclusions: Obesity may be the risk of the progression of paroxysmal to sustained AF. The progression may be associated with increased risk of ischemic stroke in both obese and non-obese patients, but the risk of hospitalization for HF might be lower in patients with obesity as compared with those without obesity.

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 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: 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: Hyperlipidemia is a well-established risk factor for cardiovascular disease. However, low cholesterol is also reported to be associated with poor outcome in chronic disease, which is called “cholesterol paradox”, and the impact of cholesterol level on the incidence of stroke or systemic embolism (SE) in atrial fibrillation (AF) remains unclear. Methods: The Fushimi AF Registry is a community-based prospective survey of the AF patients in Fushimi-ku, Kyoto, Japan. We obtained baseline total cholesterol level (TC) in 3,051 patients, and examined the relationship between TC and incidence of stroke/SE. Results: TC was inversely correlated with age and positively correlated with body weight. Patients with lower TC were more likely to be male, and had more diabetes, coronary artery disease, heart failure, prior stroke/SE, chronic kidney disease, and anemia. CHA 2 DS 2 -VASc score was inversely correlated with TC. Prescription of statin was higher in patients with lower TC, but that of oral anti-coagulants was not associated with TC. During the median follow-up of 1,476 days, stroke/SE occurred in 277 (9.1%) patients. After adjustment for the components of CHA 2 DS 2 -VASc score, body weight, and prescription of oral anti-coagulants and statins, TC had significant inverse association with the incidence of stroke/SE (hazard ratio (HR), 0.94; 95% confidence interval (CI) 0.91-0.98 for 10-mg/dl increase) (Table). TC was significantly associated with ischemic stroke/SE (HR, 0.95; 95% CI 0.91-0.99 for 10-mg/dl increase), but was not associated with intracranial bleeding (HR, 0.95; 95% CI 0.88-1.02 for 10-mg/dl increase). When we divided the patients into the elderly (≥75 years) and the young, low TC was a predictor for stroke/SE in the elderly (HR, 0.94; 95% CI 0.90-0.99 for 10-mg/dl increase), but was not in the young (HR, 0.95; 95% CI 0.90-1.01 for 10-mg/dl increase). Conclusions: Low TC might be an independent predictor for stroke/SE in elderly patients with AF.

Background: Atrial fibrillation (AF) patients are likely to have concomitant coronary artery disease (CAD). A new strategy of antithrombotic therapy in AF patients with stable CAD was demonstrated in recent randomized clinical trials. Now that antithrombotic therapy for AF patients with CAD has reached a major turning point, it is important to know the prognostic factors in those patients. Purpose: In this study, we investigated clinical characteristics, cardiovascular events and prognostic factors in AF patients with CAD. Methods: The Fushimi AF Registry, a community-based prospective survey, was designed to enroll all of the AF patients who visited the participating medical institutions in Fushimi-ku, Kyoto, Japan. Follow up data including prescription status were available in 4,441 patients from March 2011 to November 2019. Of 4,441 patients, 645 patients had a history of CAD at enrollment. Results: The mean age was 76.4±8.6 and 65.9% were male. Averages of CHA 2 DS 2 -VASc score and HAS-BLED score were 4.41 and 2.35, respectively. Oral anticoagulant (OAC) was prescribed in 52.9% of those patients and antiplatelet drug (APD) was prescribed in 70.4%. The combination of OAC and APD was prescribed in 36.0%. During follow-up period (median 1,495 days), cardiac death occurred in 51 patients, composite of cardiac death, myocardial infarction (MI) and stroke in 136, and major bleeding in 77 (1.8, 5.1 and 2.9 per 100 person-years, respectively). In multivariate analysis, factors associated with composite of cardiac death, MI and stroke in AF patients with CAD were low body weight ( Conclusion: In Japanese AF patients with CAD, low body weight, previous stroke, heart failure, hypertension and diabetes mellitus were associated with cardiovascular events, and anemia and thrombocytopenia were associated with major bleeding.

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.

Introduction: p300, an intrinsic histone acetyltransferase (HAT), has a crucial role in the pathological cardiac hypertrophy and the development of heart failure in vivo . Although many studies have shown a cardioprotective effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), omega-3 fatty acids, little is known about the effects of these acids on cardiac hypertrophy. Aim: This study investigated whether EPA and DHA inhibited the development of heart failure in rats with myocardial infarction (MI). Methods and Results: To investigate the effects on cardiomyocyte hypertrophy in cultured cardiomyocytes, neonatal rat cultured cardiomyocytes were stimulated with phenylephrine (PE). EPA or DHA significantly inhibited PE-induced cardiomyocyte hypertrophy. EPA and DHA repressed to the same extent PE-induced acetylation of histone H3 in cultured cardiomyocytes. An in vitro HAT assay was performed to determine the direct inhibition of p300-HAT activity. The results revealed that EPA and DHA significantly inhibited p300-HAT activity. To assess whether EPA and DHA suppress p300-HAT activity directly in cultured cardiomyocytes, p300 was overexpressed in cultured cardiomyocytes. Treatment with EPA or DHA inhibited the overexpression of p300-induced cardiomyocyte hypertrophy in cultured cardiomyocytes. MI-operated rats (FS < 40%) were randomly assigned to 3 groups: vehicle, EPA (1 g/kg) and DHA (1 g/kg). One week after MI operation, oral administrations were repeated for 6 weeks. Echocardiographic analysis demonstrated that EPA and DHA significantly improved MI-induced cardiac dysfunction. In addition, Masson's trichrome staining showed that EPA and DHA inhibit MI-induced fibrosis response in MI rats. EPA and DHA repressed MI-induced hypertrophic response gene transcriptions such as ANF and BNP with RT-PCR. Western blotting demonstrated that inhibited MI-induced H3K9 acetylation in rats . Conclusion: EPA and DHA suppressed hypertrophic responses to the same extent, through the direct inhibition of p300-HAT activity and repressed MI-induced development of heart failure.

Background: It is unknown whether fibrillation cycle length (FCL) on the surface electrocardiogram is associated with clinical outcomes in patients with atrial fibrillation (AF). Methods: The Fushimi AF Registry, a community-based prospective survey, was designed to enroll all of the AF patients in Fushimi-ku, Kyoto. The FCL was calculated using spectral analysis of the fibrillation waves on the surface electrocardiogram in 966 patients (mean age; 73.2 years, female; 40.9%, mean CHA 2 DS 2 -VASc score; 3.21) with AF at baseline. We assessed the association of FCL with the demographics and clinical outcomes. Results: Median FCL was 163.8 ms (interquartile range; 148.0, 195.0 ms). We divided the patients into 2 groups: 524 patients with FCL ≥163 ms and 442 patients with FCL2 DS 2 -VASc score (3.41 vs. 2.98; p Conclusion: The FCL on surface electrocardiogram was associated with higher mortality and incidence of hospitalization for HF in Japanese AF patients enrolled in the Fushimi AF Registry.

Background: The impact of chronic kidney disease (CKD) on the association of cardiovascular (CV) and renal biomarkers with the presence and severity of coronary artery disease (CAD) in patients with suspected CAD are unclear. Methods: Using data from a multicenter, prospective cohort of 2324 patients with suspected but no history of CAD undergoing elective coronary angiography, we assessed the impact of CKD on the association of CV and renal biomarkers with the presence and severity of CAD. Heparin-free fasting serum levels of soluble vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1), VEGF, placental growth factor (PlGF), N-terminal pro-brain natriuretic peptide (NT-proBNP), contemporary sensitive cardiac troponin-I (cTnI), high-sensitivity CRP (hs-CRP), cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) were measured in 887 CKD and 1437 non-CKD patients enrolled in the EXCEED-J study. The severity of CAD was quantified using the Gensini score. Results: The mean age (standard deviation) of the patients was 69.8 (10.8) years; 65.6% were men. Serum levels of all biomarkers except PlGF were significantly higher in CKD than in non-CKD patients. In the entire patient cohort, only natural log-transformed (Ln-) cTnI was significantly associated with CAD, multi-vessel or left main trunk disease (MVD/LMTD), and Ln-Gensini score after adjustment for potential confounders. These associations were still significant in non-CKD, but not in CKD: Ln-cTnI was significantly associated with MVD/LMTD and Ln-Gensini score, but not with CAD. Stepwise regression analyses including potential confounders and all biomarkers revealed that Ln-cTnI was independently associated with CAD, MVD/LMTD, and Ln-Gensini score in the entire cohort and in non-CKD, but not in CKD: Ln-cTnI was independently associated with MVD/LMTD and Ln-Gensini score, but not with CAD. No other biomarker exhibited an independent association with CAD, MVD/LMTD, or Ln-Gensini score in the entire cohort, in non-CKD, or in CKD. Conclusions: Among CV and renal biomarkers measured in this study, only Ln-cTnI was independently associated with the presence and severity of CAD in patients with suspected CAD. These associations were attenuated in patients with CKD.

Background: Diabetes mellitus (DM) is still significantly associated with the risk of mortality in the general population. Higher circulating growth differentiation factor 15 (GDF-15) levels are associated with the risk of mortality in the general population, in patients with DM, and in those with coronary artery disease (CAD). However, whether GDF-15 levels differ according to the diabetic status and whether DM modifies the relationship between GDF-15 and mortality in patients with stable CAD are unclear. Methods: Using data from a multicenter, prospective cohort of 1460 patients with stable CAD, we assessed the association between diabetic status and GDF-15 and the impact of DM on the association between GDF-15 levels and the risk of all-cause death. GDF-15 was measured in 797 DM and 663 non-DM patients enrolled in the ANOX Study. Results: The mean age (standard deviation [SD]) of the patients was 71.7 (9.4) years; 74.4% were men. Patients with DM exhibited significantly higher levels of GDF-15 compared to those without DM (median [interquartile range], 1472 [1049-2258] vs. 1274 [868-1874] pg/mL, respectively; P P Conclusions: Higher levels of GDF-15 were independently associated with DM in patients with stable CAD. The prognostic value of GDF-15 on mortality was pronounced in patients with DM.

Introduction: Serotonin (5-HT), a neurohormone involved in a wide range of physiological functions, has generated much interest in recent years regarding its potential role in cardiac function. It is reported that sarpogrelate, a selective 5-HT2A receptor antagonist, possesses cardioprotective effect against myocardial infarction, however, the precise molecular mechanism of the effect is still unclear. In this study, we examined the effect of sarpogrelate on pressure overload-induced development of heart failure, another heart failure model. Methods: First, primary cultured cardiomyocytes were treated with 1 μM sarpogrelate and then stimulated with various hypertrophic stimuli. Cardiomyocytes were stained with anti-actinin antibody and the surface area of the cells were measured. The phosphorylation levels of ERK1/2 and GATA4 were assessed by western blotting. Next, C57BL/6j male mice were subjected to a transverse aortic constriction (TAC) and sham operation. One day after the operation, the mice were randomly divided into 3 groups: sarpogrelate at 1 mg/kg or 5 mg/kg, and vehicle as a control. Daily oral administration was repeated for 8 weeks. Results: Sarpogrelate significantly suppressed an increase in the surface area of cardiomyocytes induced not only by 5-HT, but also by phenylephrine, angiotensin II and ET-1. Sarpogrelate suppressed phenylephrine-induced phosphorylation of ERK1/2 and GATA4. In a mice model of heart failure, echocardiographic analysis showed that 5 mg/kg sarpogrelate significantly prevented a TAC-induced increase in posterior left ventricular wall thickness and a decrease in fractional shortening at 8 weeks after the operation. One mg/kg sarpogrelate also suppressed TAC-induced increase in HW/BW ratio, myocardial cell diameter and the mRNA levels of ANF and BNP. Moreover, 1 mg/kg sarpogrelate significantly suppressed TAC-induced phosphorylation of ERK1/2. Conclusions: These results indicate that sarpogrelate significantly suppresses cardiomyocyte hypertrophy and the development of heart failure via at least, in part, by inhibition of ERK1/2/GATA4 pathway. These findings suggest that sarpogrelate may be an effective agent for heart failure therapy.

Background: Excessive alcohol intake is the risk of death, cerebrovascular event and bleeding. On the other hand, moderate drinking reduces the risk of cardiovascular event. However, the effect of alcohol consumption habit on mortality and cardiovascular event in AF patients remains unclear. Method: The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto, which is a typical urban district of Japan. We started to enroll patients from March 2011, and follow-up data were available for 4,466 patients by the end of November 2019. In the entire cohort, data of alcohol drinking were available for 2,944 patients. 834 patients drank daily, 554 socially and 1556 hardly (daily, socially and hardly group, respectively). Result: Compared with hardly groups, patients in daily and socially groups were younger, more often male, more in body weight and more likely to have persistent/permanent type AF. Daily and socially groups were less likely to have heart failure, chronic kidney disease and had lower CHA 2 DS 2 -VASc score. Hypertension and prior stroke/SE were the highest in daily group. Pulse rate, diabetes mellitus and prior bleeding were comparable between three groups. During the median follow-up of 1,482 days, the incidence rate of stroke/SE was significantly higher in hardly group than daily or socially groups (daily vs. socially vs. hardly: 1.19 vs. 1.11 vs. 1.49 per 100 person-years, respectively, log rank p=0.006). The incidence rates of all-cause death (2.45 vs. 3.15 vs. 4.44, p Conclusion: As compared with patients drinking alcohol, the risk of stroke/SE, all-cause death, cardiac death in hardly drinking patients were significantly higher. Daily drinking was significantly associated with lower risk of all-cause death and cardiac death.

Introduction: Anemia has been reported to be associated with poor prognosis in patients with atrial fibrillation (AF). Concomitant thrombocytopenia (TP) may or may not affect the prescription of antithrombotic drugs and clinical outcomes in these patients. Methods: The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto. We defined TP as platelet counts less than 150,000/μL and anemia as hemoglobin less than 11 g/dL. Among 666 patients with anemia, we compared the clinical backgrounds and outcomes of those with TP (n=183) and those without (n=483). Results: Compared with patients without TP, patients with TP were more likely to have chronic kidney disease (75.4% vs. 61.8%, p=0.001), and less likely to have hypertension (58.5% vs. 67.0%, p=0.0393), and less likely to have dyslipidemia (27.3% vs. 38.3%, p=0.0079). Age, sex, body weight, CHADS 2 score, CHA 2 DS 2 -VASc score, HAS-BLED score, and previous major bleeding were comparable between the groups. Furthermore, prescription of anti-thrombotic drugs was comparable (Figure A). On Kaplan-Meier analysis, the incidence of all-cause death was higher in TP group (hazard ratio [HR] 1.52; 95% confidence interval [CI] 1.20-1.91, p Conclusions: Concomitant TP in AF patients with anemia did not affect the prescription of antithrombotic drugs, and was independently associated with all-cause death in the Fushimi AF Registry.

Background: Growth differentiation factor 15 (GDF-15) is a stress responsive cytokine of the transforming growth factor superfamily. Circulating levels of GDF-15 are elevated in various conditions including anemia and stable coronary artery disease (CAD), and associated with the risk of mortality in patients with stable CAD. However, whether anemia modifies the relationship between GDF-15 and mortality in patients with stable CAD is unknown. Methods: Using data from a multicenter, prospective cohort of 1460 patients with stable CAD, we assessed the association between anemic status and GDF-15 and the impact of anemia on the association between GDF-15 levels and the risk of all-cause death. GDF-15 was measured in 564 anemic and 896 non-anemic patients enrolled in the ANOX Study. Results: The mean age (standard deviation [SD]) of the patients was 71.7 (9.4) years; 74.4% were men. Patients with anemia exhibited significantly higher levels of GDF-15 compared to those without anemia (median [interquartile range], 1953 [1302-3110] vs. 1175 [838-1579] pg/mL, respectively; P P Conclusions: Higher levels of GDF-15 were independently associated with anemia in patients with stable CAD. The prognostic value of GDF-15 on mortality was pronounced in patients with anemia.

The impact of catheter ablation (CA) on the long-term clinical outcomes in atrial fibrillation (AF) are unclear due to limited cohort investigations. The Fushimi AF Registry is a community-based prospective survey of patients with AF in Fushimi-ku, Kyoto, Japan. Of 4465 patients enrolled between March 2011 and July 2019, analyses were performed on 2639 patients (492 patients who underwent CA and 2147 patients who received standard rhythm- and/or rate-control drug therapy at baseline). We compared the baseline characteristics and the incidence of major adverse cardiovascular events (MACE: the composite of cardiovascular death, heart failure hospitalization, myocardial infarction, ischemic stroke or systemic embolism), and all-cause mortality during the follow-up using propensity score matching. After entering 20 covariates in the current matching analysis, 342 patients who underwent CA and 342 matched patients who received drug therapy, with a median follow-up of 1865 days, were included. The patients who underwent CA were significantly associated with lower incidence of MACE (hazard ratio (HR) 0.56, 95% confidential interval (CI) 0.36–0.86; P = 0.0077), and all-cause mortality (HR 0.47, 95% CI 0.29–0.75; P = 0.0016). CA was associated with lower incidences of MACE and all-cause mortality for patients with AF as compared with those who received drug therapy. The most common event of MACE in patients who underwent CA was heart failure hospitalization. URL: http://www.umin.ac.jp/ctr/index.htm UMIN000005834.

Background Atrial fibrillation (AF) increases the risk of death, stroke/systemic embolism and heart failure (HF). Plasma natriuretic peptide (NP) level is an important prognostic marker in HF patients. However, little is known regarding the prognostic significance of plasma NP level in AF patients without HF. Purpose The aim of this study is to investigate the relationship between plasma NP level and clinical outcomes such as all-cause death, stroke/systemic embolism and HF hospitalization during follow-up period in AF patients without HF. Methods The Fushimi AF Registry is a community-based prospective survey of AF patients in our city. The inclusion criterion of the registry is the documentation of AF at 12-lead electrocardiogram or Holter monitoring at any time, and there are no exclusion criteria. We started to enroll patients from March 2011, and follow-up data were available for 4,466 patients by the end of November 2019. From the registry, we excluded 1,220 patients without a pre-existing HF (defined as having one of the following; prior hospitalization for HF, New York Heart Association class ≥2, or left ventricular ejection fraction Results Of 1,189 patients, the mean age was 72.1±10.2 years, 454 (38%) were female and 684 (58%) were paroxysmal AF. The mean CHADS2 and CHA2DS2-VASc score were 1.6±1.1 and 2.9±1.5, respectively. Oral anticoagulants were prescribed in 671 (56%) at baseline. The median (interquartile range) BNP and N-terminal pro-BNP level were 84 (38, 176) and 500 (155, 984) pg/ml, respectively. Patients with high plasma NP level were older, and demonstrated lower prevalence of paroxysmal AF, higher CHADS2 and CHA2DS2-VASc scores and higher prevalence of chronic kidney disease and oral anticoagulants prescription (all P Conclusion Plasma NP level is a significant prognostic marker for all-cause death, stroke/systemic embolism and HF hospitalization in AF patients without HF, suggesting the importance of measuring plasma NP level in AF patients even without HF. Figure 1 Funding Acknowledgement Type of funding source: None

Background Atrial fibrillation (AF) commonly progresses from paroxysmal type to sustained type in the natural course of the disease, and we previously demonstrated that the progression of AF was associated with increased risk of clinical adverse events. There are some patients, though less frequently, who regress from sustained to paroxysmal AF, but the clinical impact of the regression of AF remains unknown. Purpose We sought to investigate whether regression from sustained to paroxysmal AF is associated with better clinical outcomes. Methods Using the dataset of the Fushimi AF Registry, patients who were diagnosed as sustained (persistent or permanent) AF at baseline were studied. Conversion of sustained AF to paroxysmal AF during follow-up was defined as regression of AF. Major adverse cardiac events (MACE) were defined as the composite of cardiac death, stroke, and hospitalization for heart failure (HF). Event rates were compared between the patients with and without regression of AF. In patients with sustained AF at baseline, predictors of MACE were identified using Cox proportional hazards model. Results Among 2,253 patients who were diagnosed as sustained AF at baseline, regression of AF was observed in 9.0% (202/2,253, 2.0 per 100 patient-years) during a median follow-up of 4.0 years. Of these, 24.3% (49/202, 4.6 per 100 patient-years) of the patients finally recurred to sustained AF during follow-up. The proportion of asymptomatic patients was lower in patients with regression of AF than those without (with vs without regression; 49.0% vs 69.5%, p Conclusion Regression from sustained to paroxysmal AF was associated with a lower incidence of adverse cardiac events. Funding Acknowledgement Type of funding source: None

Background Hypertension is one of the major risk factors of cardiovascular events in patients with atrial fibrillation (AF). However, relationship between diastolic blood pressure (DBP) and cardiovascular events in AF patients remains unclear. Methods The Fushimi AF Registry is a community-based prospective survey of AF patients in Japan. Follow-up data were available in 4,466 patients, and 4,429 patients with available data of DBP were examined. We divided the patients into three groups; G1 (DBP Results The proportion of female was grater in G1 group, and the patients in G1 group were older and had higher prevalence of heart failure (HF), diabetes mellitus (DM), chronic kidney disease (CKD). Prescription of beta blockers was higher in G1 group, but that of renin-angiotensin system-inhibitors and calcium channel blocker was comparable. During the median follow-up of 1,589 days, in Kaplan-Meier analysis, the incidence rates of cardiovascular events (composite of cardiac death, ischemic stroke and systemic embolism, major bleeding and HF hospitalization during follow up) were higher in G1 group and G3 group than G2 group (Figure 1). When we divided the patients based on the systolic blood pressure (SBP) at baseline (≥130 mmHg or Conclusion In Japanese patients with AF, DBP exhibited J curve association with higher incidence of cardiovascular events. Funding Acknowledgement Type of funding source: None

Background Vascular endothelial growth factor D (VEGF-D) is a secreted glycoprotein that can act as lymphangiogenic and angiogenic growth factors through binding to its specific receptors, VEGFR-3 and VEGFR-2. VEGF-D signaling via VEGFR-3 plays an important role in lipoprotein metabolisms which may contribute to coronary artery disease (CAD). We recently reported that serum levels of VEGF-D are independently associated with mortality in patients with suspected or known CAD. However, the impact of glucose tolerance status on the relationship between VEGF-D and mortality in patients with suspected CAD is unclear. Methods Serum VEGF-D levels were measured in 1,717 patients with suspected 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. After excluding 67 patients with no HbA1c data, 1,650 patients were divided into 3 groups according to the glucose tolerance status: diabetes (DM, n=693), prediabetes (preDM, n=541) defined as an HbA1c of 5.7 to 6.4%, and normal glucose tolerance (NGT, n=416) defined as an HbA1c of 5.6% or less. The outcomes were total death, 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, 80 DM, 45 preDM, and 30 NGT patients died from any cause, 24 DM, 13 preDM, and 12 NGT died from CV disease, and 54 DM, 30 preDM, and 19 NGT developed MACE. After adjustment for established risk factors, VEGF-D levels were significantly associated with total death (hazard ratio [HR] for 1-SD increase, 1.28; 95% confidence interval [CI], 1.12–1.47), but not with CV death (HR, 1.20; 95% CI, 0.93–1.52) or MACE (HR, 1.23; 95% CI, 0.997–1.48) in DM; VEGF-D levels were not significantly associated with total death (HR, 0.97; 95% CI, 0.70–1.34), CV death (HR, 1.39; 95% CI, 0.92–2.11), or MACE (HR, 1.09; 95% CI, 0.74–1.50) in preDM; VEGF-D levels were not significantly associated with total death (HR, 1.34; 95% CI, 0.98–1.84), CV death (HR, 1.32; 95% CI, 0.78–2.13), or MACE (HR, 1.01; 95% CI, 0.66–1.46) in NGT. 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-D levels further improved the prediction of total death (P=0.040 for continuous net reclassification improvement [NRI], P=0.007 for integrated discrimination improvement [IDI]), but not that of CV death or MACE in DM, while it did not significantly improved the prediction of total death, CV death, or MACE either in preDM or in NGT. Conclusions The VEGF-D level was independently associated with total death in DM, but not in preDM or in NGT. The relationship between VEGF-D and total mortality may depend on the presence of DM in patients with suspected CAD. 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.

Background Whether circulating growth differentiation factor 15 (GDF‐15) levels differ according to smoking status and whether smoking modifies the relationship between GDF‐15 and mortality in patients with coronary artery disease are unclear. Methods and Results Using data from a multicenter, prospective cohort of 2418 patients with suspected or known coronary artery disease, we assessed the association between smoking status and GDF‐15 and the impact of smoking status on the association between GDF‐15 and all‐cause death. GDF‐15 was measured in 955 never smokers, 1035 former smokers, and 428 current smokers enrolled in the ANOX Study (Development of Novel Biomarkers Related to Angiogenesis or Oxidative Stress to Predict Cardiovascular Events). Patients were followed up during 3 years. The age of the patients ranged from 19 to 94 years; 67.2% were men. Never smokers exhibited significantly lower levels of GDF‐15 compared with former smokers and current smokers. Stepwise multiple linear regression analysis revealed that the log‐transformed GDF‐15 level was independently associated with both current smoking and former smoking. In the entire patient cohort, the GDF‐15 level was significantly associated with all‐cause death after adjusting for potential clinical confounders. This association was still significant in never smokers, former smokers, and current smokers. However, GDF‐15 provided incremental prognostic information to the model with potential clinical confounders and the established cardiovascular biomarkers in never smokers, but not in current smokers or in former smokers. Conclusions Not only current, but also former smoking was independently associated with higher levels of GDF‐15. The prognostic value of GDF‐15 on mortality was most pronounced in never smokers among patients with suspected or known coronary artery disease.

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 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 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.

Background Heart failure with preserved ejection fraction (HFpEF) is an important comorbidity of atrial fibrillation (AF). However, it is sometimes difficult to detect HFpEF among AF patients with preserved EF, since AF and HF share similar symptoms. Purpose The aim of this study was to identify factors associated with having HFpEF in AF patients with preserved EF, and derive a new score for HFpEF in AF patients. Methods The Fushimi AF Registry is a community-based prospective survey of the AF patients in Fushimi-ku, Kyoto, Japan. Follow-up data were available for 4,466 patients, and 3,083 patients had preserved EF (≥50%). Of the 3,083 patients, 444 had prior HF hospitalization at baseline and we defined these patients as HFpEF. We examined the factors associated with having HFpEF, and derived a new score for detecting HFpEF in AF patients. Thereafter, we validated this score in patients without prior HF hospitalization. Result The mean age of the patients with EF ≥50% was 73.6 years, and 41.3% were female. Compared with the patients without prior HF hospitalization, HFpEF patients were older, more often female, less in body weight, had more heart disease (valvular heart disease, cardiomyopathy, old myocardial infarction, and coronary artery disease), chronic kidney diseases (CKD), anemia (Hb 45 mm), and dilation of cardio-thoracic ratio (CTR) (>54%) at baseline. In multivariate analysis, heart diseases, CKD, sustained AF, dilatation of CTR, left atrial enlargement, and anemia were significantly associated with HFpEF (Table 1). We derived a new score to diagnose HFpEF in AF patients (2 points for heart diseases, 1 point for CKD, sustained AF, dilatation of CTR, left atrial enlargement, and anemia; range 0 to 7 points). In a receiver-operating characteristic curve, optimal cut-off point for detecting HFpEF was 3 (Figure 1). We validated this score in patients without prior hospitalization for HF (n=2,639). Of these, 298 patients had HF symptoms of NYHA 2–4 (Symptomatic-HF), and 2,341 patients had neither prior HF hospitalization nor HF symptoms (No-HF). Notably, 207 patients (69.5%) in symptomatic-HF group and 748 patients (32.0%) in No-HF group were classified into HFpEF based on this new score. Furthermore, patients diagnosed as HFpEF by this score had higher incidence of new hospitalization for HF during the follow-up in both symptomatic-HF group and No-HF group. (Figure 2). Conclusion We derived a new score to diagnose HFpEF in AF patients based on the presence of prior HF hospitalization (2 points for heart diseases, 1 point for CKD, sustained AF, dilatation of CTR, left atrial enlargement, and anemia). In patients without prior HF hospitalization, sizable number of patients had high HFpEF score (≥3), and those patients showed higher incidence of new HF hospitalization. Funding Acknowledgement Type of funding source: None

Background We previously reported that valvular heart disease (VHD) was not at the significant risk of stroke/systemic embolism (SE), but was associated with an increased risk of hospitalization for heart failure (HF) in Japanese atrial fibrillation patients. However, the impact of combined VHD on clinical outcomes has been little known. Purpose The aim of this study is to investigate the prevalence of combined VHD and its clinical characteristics and impact on outcomes such as stroke/SE, all-cause death, cardiac death and hospitalization for HF. Method The Fushimi AF Registry is a community-based prospective survey of AF patients in one of the wards of our city which is a typical urban district of Japan. We started to enroll patients from March 2011, and follow-up data were available for 4,466 patients by the end of November 2019. In the entire cohort, echocardiography data were available for 3,574 patients. 68 AF patients with prosthetic heart valves were excluded and we compared clinical characteristics and outcomes between 488 single VHD (103 Aortic valve disease (AVD), 315 mitral valve disease (MVD), 70 tricuspid valve disease (TVD)) and 158 combined VHD (46 AVD and MVD, 11 AVD and TVD, 66 MVD and TVD, 35 AVD and MVD and TVD). Result Compared with single VHD, patients with combined VHD were older (combined vs. single VHD: 78.5 vs. 76.0 years, respectively; p During the median follow-up of 1,474 days, the incidence rate of stroke/SE was not significantly different between the two groups (1.58 vs. 1.89 per 100 person-years, respectively, log rank p=0.10). The incidence rate of all-cause death (7.35 vs. 5.33, p=0.65), cardiac death (1.20 vs. 0.99, p=0.91) and hospitalization for HF (5.55 vs. 4.43, p=0.53) were also not significantly different. We previously reported AVD had significant impacts on cardiac adverse outcomes in AF patients, and we further analyzed event rates between combined VHD including AVD (AVD and MVD/TVD) and without AVD (MVD and TVD). Combined VHD with AVD group had higher incidence rate of all-cause death (10.7 vs. 5.79, p=0.03) than that without AVD group. However, the incidence rate of stroke/SE (1.98 vs. 1.56, p=0.59), cardiac death (0.98 vs. 1.14, p=0.68), hospitalization for HF (8.03 vs. 5.38, p=0.17) were not significantly different between the two groups. Conclusion As compared with single VHD, the risk of stroke/SE, all-cause death, cardiac death and hospitalization for HF in combined VHD was not significantly different. Among patients with combined VHD, those having AVD had higher incidence rate of all-cause death than those without AVD. Figure 1 Funding Acknowledgement Type of funding source: None

Background Growth differentiation factor 15 (GDF-15) is a stress-responsive cytokine that plays an important role in the regulation of the inflammatory response, growth and cell differentiation. An elevated GDF-15 was found in various conditions including anemia and stable coronary artery disease (CAD), and it was reported to predict mortality and cardiovascular (CV) events in general population and in patients with established CAD. However, the impact of anemia on the relationships of GDF-15 with mortality and CV events in patients with suspected or known CAD is unclear. Methods Serum GDF-15 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 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, GDF-15 levels were significantly associated with all-cause death (hazard ratio [HR] for 1-SD increase, 1.75; 95% confidence interval [CI], 1.51–2.04), CV death (HR, 1.67; 95% CI, 1.30–2.13), and MACE (HR, 1.46; 95% CI, 1.18–1.81) in anemic, while GDF-15 levels were also significantly associated with all-cause death (HR, 1.47; 95% CI, 1.27–1.69), CV death (HR, 1.56; 95% CI, 1.18–1.99), and MACE (HR, 1.25; 95% CI, 1.004–1.50) 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 GDF-15 levels further improved the prediction of all-cause death (P Conclusions The GDF-15 level significantly improved the prediction of all-cause death, CV death, and MACE in anemic, but not in non-anemic patients with suspected or known CAD. The relationships of GDF-15 with mortality and CV events seem to be remarkable in 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.

Background Patients with atrial fibrillation (AF) commonly coexist with chronic kidney disease (CKD). Non-vitamin K antagonist oral anticoagulants (NOAC) are recommended for stroke prevention in patients with non-valvular atrial fibrillation (AF), and worsening renal function (WRF) as well as CKD is an important issue in using NOAC. However, little is known about the clinical outcomes of patients after WRF. Purpose We aimed to investigate outcomes after WRF in AF patients. Methods The Fushimi AF Registry is a community-based prospective survey of the AF patients in our city. Follow-up data including prescription status were available for 4,441 patients. Of them, 1,890 patients who have baseline and at least 1 follow-up creatinine clearance (CrCl) measurements, estimated by the Cockcroft-Gault formula, were analyzed in the present study. WRF was defined as a decrease of ≥20% from baseline CrCl measurement at any time point during follow-up. We evaluated demographics and outcomes after WRF in AF patients. Results During the median follow-up period of 2,194 days, mean CrCl decrease of 2.2 ml/min/year was observed and WRF occurred in 981 patients (51.9%). Patients with WRF were significantly more often female (with vs. without WRF; 40.3% vs. 35.4%; p=0.03), older (73.4 vs. 71.1 years of age; p Conclusions AF patients after WRF had higher incidence of various adverse events. Incidence of Adverse Outcomes Funding Acknowledgement Type of funding source: Other. Main funding source(s): The Practical Research Project for Life-Style related Diseases including Cardiovascular Diseases and Diabetes Mellitus from Japan Agency for Medical Research and Development. Boehringer Ingelheim, Bayer Healthcare, Pfizer, Bristol-Myers Squibb, Astellas Pharma, AstraZeneca, Daiichi-Sankyo, Novartis Pharma, MSD, Sanofi-Aventis, and Takeda Pharmaceutical.

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 chronic kidney disease (CKD) on the relationship between VEGF-C and mortality in patients with suspected CAD is unclear. Methods Serum VEGF-C levels were measured in 1,717 patients with suspected but no history of 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. Patients were divided into 2 groups according to the presence (CKD, n=674) or absence (non-CKD, n=1,043) of CKD. 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, 95 CKD and 66 non-CKD patients died from any cause, 37 CKD and 13 non-CKD died from CV disease, and 61 CKD and 43 non-CKD 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, 0.72; 95% confidence interval [CI], 0.57–0.90) and CV death (HR, 0.69; 95% CI, 0.48–0.97), but not with MACE (HR, 0.78; 95% CI, 0.60–1.03) in CKD, while VEGF-C levels were significantly and inversely associated with all-cause death (HR, 0.69; 95% CI, 0.52–0.91), but not with CV death (HR, 0.91; 95% CI, 0.50–1.66) or MACE (HR, 1.09; 95% CI, 0.81–1.44) in non-CKD. 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=0.047 for continuous net reclassification improvement [NRI], P=0.048 for integrated discrimination improvement [IDI]), but not that of CV death (P=0.016 for NRI, P=0.245 for IDI) or MACE (P=0.166 for NRI, P=0.311 for IDI) in CKD, whereas the addition of VEGF-C levels did not improve the prediction of all-cause death (P=0.053 for NRI, P=0.012 for IDI), CV death (P=0.864 for NRI, P=0.602 for IDI) or MACE (P=0.999 for NRI, P=0.154 for IDI) in non-CKD. Conclusions The VEGF-C level inversely and independently predicted all-cause mortality in CKD, but not in non-CKD patients with suspected CAD. The inverse relationship between VEGF-C and all-cause mortality in patients with suspected CAD seems to be remarkable in the presence of CKD. 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.

BACKGROUND Heart rate (HR) is an important factor in atrial fibrillation (AF); however, it remains unclear whether the impact of HR differs between paroxysmal AF and sustained (persistent and permanent) AF.Methods and Results:The association of resting HR during AF with adverse events (composite of all-cause death, hospitalization for heart failure, stroke/systemic embolisms, myocardial infarction, and arrhythmic events) in 1,064 paroxysmal and 1,610 sustained AF patients from the Fushimi AF Registry were investigated. These patients were divided into 4 groups based on their resting HR; ≥110 beats/min (bpm), 80-109 bpm, 60-79 bpm, and