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Background: Polypharmacy is associated with an increased risk of adverse events due to the higher number of drugs used. This is particularly notable in patients with chronic coronary syndrome (CCS), who are known to use a large number of drugs. Therefore, we investigated polypharmacy in patients with CCS, using CLIDAS, a multicenter database of patients who underwent percutaneous coronary intervention. Method and results: Between 2017 and 2020, 1411 CCS patients (71.5 ± 10.5 years old; 77.3 % male) were enrolled. The relationship between cardiovascular events occurring during the median follow-up of 514 days and the number of drugs at the time of PCI was investigated. The median number of drugs prescribed was nine. Major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, stroke, heart failure, transient ischemic attack, or unstable angina, occurred in 123 patients, and all-cause mortality occurred in 68 patients. For each additional drug, the adjusted hazard ratios for MACE and all-cause mortality increased by 2.069 (p = 0.003) and 1.102 (p = 0.010). The adjusted hazard ratios for MACE and all-cause mortality were significantly higher in the group using nine or more drugs compared to the group using eight or fewer drugs (1.646 and 2.253, both p

The peptide mimetic, NC114, is a promising anticancer compound that specifically kills colorectal cancer cells without affecting normal colon epithelial cells. In our previous study, we observed that NC114 inhibited the Wnt/β‐catenin pathway, with significant downregulation of both Ser 675‐phosphorylated β‐catenin and its target genes, cyclin D1 and survivin. However, the molecular mechanism responsible for its cytotoxic effect has not yet been fully characterized. In the present study, we demonstrated that NC114 prevented cell cycle progression from S to G2/M phase by downregulating cell cycle‐related gene expression, and also induced growth arrest in SW480 and HCT‐116 colorectal cancer cells. A novel covariation network analysis combined with transcriptome analysis revealed a series of signaling cascades affected by NC114 treatment, and identified protein kinase C‐δ (PKCδ) and forkhead box protein M1 (FOXM1) as important regulatory factors for NC114‐induced growth arrest. NC114 treatment inhibits the activation of PKCδ and its kinase activity, which suppresses MEK/ERK signaling. Attenuated MEK/ERK signaling then results in a reduction in FOXM1 phosphorylation and subsequent nuclear translocation of FOXM1 and β‐catenin. Consequently, formation of a T‐cell factor‐4 (TCF4)/β‐catenin transcription complex in the nucleus is inhibited and transcription of its target genes, such as cell cycle‐related genes, is downregulated. The efficacy of NC114 on tumor growth was confirmed in a xenograft model. Collectively, elucidation of the mechanism by which NC114 induces growth arrest in colorectal cancer cells should provide a novel therapeutic strategy for colorectal cancer treatment.

Metabolic dysfunction-associated steatohepatitis (MASH), characterized by progressive inflammation and fibrosis, evolves from metabolic dysfunction-associated steatotic liver disease and significantly heightens the risk of cirrhosis and hepatocellular carcinoma. Understanding metabolic pathways that influence MASH progression is crucial for developing targeted therapies. Non-targeted metabolomics offer a comprehensive view of metabolic alterations, enabling identification of novel biomarkers and pathways without preconceived ideas. Conversely, targeted metabolomics deliver precise and reproducible measurements, focusing on predefined metabolites to accurately quantify established pathways. This study utilized hepatocyte-specific PTEN knockout mice as a model to explore metabolic shifts associated with MASH. By integrating non-targeted metabolomics and targeted metabolomics, we analyzed liver samples from three groups: normal, pathological (MASH-affected), and MASH-affected, but treated with apomorphine, an antioxidant and recently reported ferroptosis inhibitor with potential therapeutic effects. Metabolic profiling identified lysophospholipids (LPLs) as significantly altered metabolites, with elevated levels in the MASH model and a notable reduction after apomorphine treatment. This suggests that LPLs are central to the etiology of MASH and may serve as targets for therapeutic intervention. Our findings underscore the effectiveness of apomorphine in modulating disease-specific metabolic disruptions, offering insights into its potential as a treatment for human MASH.

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

Abstract Background Aggressive lipid lowering by high-dose statin treatment has been established for the secondary prevention of coronary artery disease (CAD). Regarding the low-density lipoprotein cholesterol (LDL-C) level, however, the “The lower is the better” concept has been controversial to date. We hypothesized that there is an optimal LDL-C level, i.e., a “threshold” value, below which the incidence of cardiovascular events is no longer reduced. We undertook a subanalysis of the REAL-CAD study to explore whether such an optimal target LDL-C level exists by a novel analysis procedure to verify the existence of a monotonic relationship. Methods For a total of 11,105 patients with CAD enrolled in the REAL-CAD study, the LDL-C level at 6 months after randomization and 5-year cardiovascular outcomes were assessed. We set the “threshold” value of the LDL-C level under which the hazards were assumed to be constant, by including an artificial covariate max (0, LDL-C − threshold) in the Cox model. The analysis was repeated with different LDL-C thresholds (every 10 mg/dl from 40 to 100 mg/dl) and the model fit was assessed by log-likelihood. Results For primary outcomes such as the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization, the model fit assessed by log-likelihood was best when a threshold LDL-C value of 70 mg/dl was assumed. And in the model with a threshold LDL-C ≥ 70 mg/dl, the hazard ratio was 1.07 (95% confidence interval 1.01–1.13) as the LDL-C increased by 10 mg/dl. Therefore, the risk of cardiovascular events decreased monotonically until the LDL-C level was lowered to 70 mg/dl, but when the level was further reduced, the risk was independent of LDL-C. Conclusions Our analysis model suggests that a “threshold” value of LDL-C might exist for the secondary prevention of cardiovascular events in Japanese patients with CAD, and this threshold might be 70 mg/dl for primary composite outcomes. Trial registration http://www.clinicaltrials.gov . Unique identifier: NCT01042730.

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

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

Abstract Pathogenic variants in myosin heavy chain (Myh11) cause familial thoracic aortic aneurysms and dissections (FTAAD). However, the underlying pathological mechanisms remain unclear because of a lack of animal models. In this study, we established a mouse model with Myh11 K1256del, the pathogenic variant we found previously in two FTAAD families. The Myh11 ∆K/∆K aorta showed increased wall thickness and ultrastructural abnormalities, including weakened cell adhesion. Notably, the Myh11 ∆K/+ mice developed aortic dissections and intramural haematomas when stimulated with angiotensin II. Mechanistically, integrin subunit alpha2 (Itga2) was downregulated in the Myh11 ∆K/∆K aortas, and the smooth muscle cell lineage cells that differentiated from Myh11 ∆K/∆K induced pluripotent stem cells. The contractility of the Myh11 ∆K/∆K aortas in response to phenylephrine was also reduced. These results imply that the suboptimal cell adhesion indicated by Itga2 downregulation causes a defect in the contraction of the aorta. Consequently, the defective contraction may increase the haemodynamic stress underlying the aortic dissections.

Heart failure with reduced ejection fraction (HFrEF) is characterized not only by reduced left ventricular ejection fraction (EF) but is also combined with symptoms such as dyspnea, fatigue, and edema. Several pharmacological interventions have been established. However, a treatment targeting a novel pathophysiological mechanism is still needed. Evidence indicating that inhibition of pyruvate dehydrogenase kinase 4 (PDK4) may be cardioprotective has been accumulating. Thus, we focused on vitamin K3 and used its framework as a new PDK4 inhibitor skeleton to synthesize new PDK4 inhibitors that show higher activity than the existing PDK4 inhibitor, dichloroacetic acid, and tested their cardioprotective effects on a mouse heart failure model. Among these inhibitors, PDK4 inhibitor 8 improved EF the most, even though it did not reverse cardiac fibrosis or wall thickness. This novel, potent PDK4 inhibitor may improve EF of failing hearts by regulating bioenergetics via activation of the tricarboxylic acid cycle.

BackgroundThe causal relationship between hyperuricemia and cardiovascular diseases is still unknown. We hypothesized that hyperuricemic patients after percutaneous coronary intervention (PCI) had a higher risk of major adverse cardiovascular events (MACE).MethodsThis was a large-scale multicenter cohort study. We enrolled patients with chronic coronary syndrome (CCS) after PCI between April 2013 and March 2019 using the database from the Clinical Deep Data Accumulation System (CLIDAS), and compared the incidence of MACE, defined as a composite of cardiovascular death, myocardial infarction, and hospitalization for heart failure, between hyperuricemia and non-hyperuricemia groups.ResultsIn total, 9,936 patients underwent PCI during the study period. Of these, 5,138 patients with CCS after PCI were divided into two group (1,724 and 3,414 in the hyperuricemia and non-hyperuricemia groups, respectively). The hyperuricemia group had a higher prevalence of hypertension, atrial fibrillation, history of previous hospitalization for heart failure, and baseline creatinine, and a lower prevalence of diabetes than the non-hyperuricemia group, but the proportion of men and age were similar between the two groups. The incidence of MACE in the hyperuricemia group was significantly higher than that in the non-hyperuricemia group (13.1 vs. 6.4%, log-rank P < 0.001). Multivariable Cox regression analyses revealed that hyperuricemia was significantly associated with increased MACE [hazard ratio (HR), 1.52; 95% confidential interval (CI), 1.23–1.86] after multiple adjustments for age, sex, body mass index, estimated glomerular filtration rate, left main disease or three-vessel disease, hypertension, diabetes mellitus, dyslipidemia, history of myocardial infarction, and history of hospitalization for heart failure. Moreover, hyperuricemia was independently associated with increased hospitalization for heart failure (HR, 2.19; 95% CI, 1.69–2.83), but not cardiovascular death or myocardial infarction after multiple adjustments. Sensitive analyses by sex and diuretic use, B-type natriuretic peptide level, and left ventricular ejection fraction showed similar results.ConclusionCLIDAS revealed that hyperuricemia was associated with increased MACE in patients with CCS after PCI. Further clinical trials are needed whether treating hyperuricemia could reduce cardiovascular events or not.

Despite remarkable recent progress in developing anti-cancer agents, outcomes of patients with solid tumors remain unsatisfactory. In general, anti-cancer drugs are systemically administered through peripheral veins and delivered throughout the body. The major problem with systemic chemotherapy is insufficient uptake of intravenous (IV) drugs by targeted tumor tissue. Although dose escalation and treatment intensification have been attempted in order to increase regional concentrations of anti-tumor drugs, these approaches have produced only marginal benefits in terms of patient outcomes, while often damaging healthy organs. To overcome this problem, local administration of anti-cancer agents can yield markedly higher drug concentrations in tumor tissue with less systemic toxicity. This strategy is most commonly used for liver and brain tumors, as well as pleural or peritoneal malignancies. Although the concept is theoretically reasonable, survival benefits are still limited. This review summarizes clinical results and problems and discusses future directions of regional cancer therapy with local administration of chemotherapeutants.

Cardiac immune cells play various roles in the maintenance of homeostasis and diseases in the heart. Here the authors show that cardiac resident macrophages are a critical regulator of cardiac impulse conduction through amphiregulin production, contributing to the prevention of sudden death.

Abstract Objectives Gastrointestinal endoscopic procedures have a risk to transmit severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) through aerosols. Little information is available on the seroprevalence of SARS‐CoV‐2 antibodies among healthcare workers (HCWs) in endoscopy units. Thus, the seroprevalence was examined in HCWs who do and do not participate in gastrointestinal endoscopy. Methods A total of 382 HCWs at Jichi Medical University Hospital were enrolled in this study through March 2021. Among 382 HCWs, 63 are in the endoscopy unit. Serum antibody levels against SARS‐CoV‐2 were determined by immunochromatography, chemiluminescent immunoassay (CLIA), electric CLIA (ECLIA), and chemiluminescence microparticle immunoassay (CMIA). HCWs in the endoscopy unit underwent testing up to three times. We defined antibody‐positive as when at least one test was positive. Results The seroprevalence of SARS‐CoV‐2 antibodies in 63 HCWs in the endoscopy unit was 0%–1.9%, 0%–1.7%, and 0%–1.7% during the first (Ap–May 2020), second (Jun–Nov 2020), and third intervals (Dec 2020–Mar 2021), respectively. This seroprevalence was comparable to that of other HCWs not involved with gastrointestinal endoscopy. Two HCWs in the endoscopy unit were positive for antibodies: one was ECLIA‐positive and the another was CMIA‐positive. The ECLIA‐positive HCW was PCR negative and converted to negative for the second and third tests. Another HCW was CMIA‐positive at all three evaluations and the titers were unchanged. No HCWs in the endoscopy unit contracted a SARS‐CoV‐2 infection. Conclusions The seroprevalence of SARS‐CoV‐2 antibodies was low among HCWs in the endoscopy unit through March 2021 (UMIN000039997).

Abstract Aims The aim of this study was to investigate whether ethnicity influences the associations between trimethylamine N‐oxide (TMAO) levels and heart failure (HF) outcomes. Methods and results Trimethylamine N‐oxide levels were measured in two cohorts with acute HF at two sites. The UK Leicester cohort consisted mainly of Caucasian (n = 842, 77%) and South Asian (n = 129, 12%) patients, whereas patients in the Japanese cohort (n = 116, 11%) were all Japanese. The primary endpoint was the measurement of all‐cause mortality and/or HF rehospitalization within 1 year post‐admission. Association of TMAO levels with outcome was compared in the entire population and between ethnic groups after adjustment for clinical parameters. TMAO levels were significantly higher in Japanese patients [median (interquartile range): 9.9 μM (5.2–22.8)] than in Caucasian [5.9 μM (3.6–10.8)] and South Asian [4.5 μM (3.1–8.4)] (P

Abstract Background Previous studies have reported that being overweight, obese, or underweight is a risk factor for ischemic cardiovascular disease (CVD); however, CVD also occurs in subjects with ideal body mass index (BMI). Recently, the balance of n-3/n-6 polyunsaturated fatty acids (PUFAs) has received attention as a risk marker for CVD but, so far, no study has been conducted that investigates the association between BMI and the balance of n-3/n-6 PUFAs for CVD risk. Methods We evaluated the association between n-3/n-6 PUFA ratio and acute coronary syndrome (ACS) in three BMI-based groups (

Objectives: To evaluate condition-specific antibiotic prescription rates and the appropriateness of antibiotic use in outpatient settings in Japan. Methods: Using Japan’s national administrative claims database, all outpatient visits with infectious disease diagnoses were linked to reimbursed oral antibiotic prescriptions. Prescription rates stratified by age, sex, prefecture, and antibiotic category were determined for each infectious disease diagnosis. The proportions of any antibiotic prescription to all infectious disease visits and the proportions of first-line antibiotic prescriptions to all antibiotic prescriptions were calculated for each infectious disease diagnosis. Results: Of the 659 million infectious disease visits between April 2012 and March 2015, antibiotics were prescribed in 266 million visits (704 prescriptions per 1000 population per year). Third-generation cephalosporins, macrolides, and quinolones accounted for 85.9% of all antibiotic prescriptions. Fifty-six percent of antibiotic prescriptions were directed toward infections for which antibiotics are generally not indicated. The diagnoses with frequent antibiotic prescription were bronchitis (184 prescriptions per 1000 population per year), viral upper respiratory infections (166), pharyngitis (104), sinusitis (52), and gastrointestinal infection (41), for which 58.3%, 40.6%, 58.9%, 53.9%, and 26.1% of visits antibiotics were prescribed, respectively. First-line antibiotics were rarely prescribed for pharyngitis (8.8%) and sinusitis (9.8%). More antibiotics were prescribed for children aged 0–9 years, adult women, and patients living in western Japan. Conclusions: Antibiotic prescription rates are high in Japan. Acute respiratory or gastrointestinal infections, which received the majority of the antibiotics generally not indicated, should be the main targets of antimicrobial stewardship intervention. Keywords: National administrative claims database, Big data, Antibiotic, Antimicrobial stewardship

Fibrosis is a hallmark of several cardiac pathologies and its underlying mechanisms are still poorly defined. Here the authors show that macrophage hypoxia signaling following transverse aortic constriction in mice suppresses the activation of cardiac fibroblasts by secreting oncostatin M.

Introduction The association among smoking history, eicosapentaenoic acid (EPA) to arachidonic acid (AA) ratio and acute coronary syndrome (ACS) is yet to be investigated. The present study aimed to clarify the association between the EPA/AA ratio and ACS prevalence in patients admitted to the cardiology department based on their smoking history. Material and Methods We enrolled 1733 patients from five cardiology divisions located in Tokyo, Japan, and measured their levels of polyunsaturated fatty acids, including EPA and AA, from January 2004 to May 2011. We assessed the association between the EPA/AA ratio and ACS in the subgroups stratified according to smoking history (never, former, current smokers) using multivariate logistic models. Results A high EPA/AA ratio was significantly associated with decreased odds of ACS among patients without a smoking history (adjusted odds ratio AOR=0.20, 95% CI: 0.04–0.86) but not in patients with a smoking history (former smoker, AOR=1.50, 95% CI: 0.44–5.03; current smoker, AOR=3.73, 95% CI: 0.34–40.6). Conclusions The EPA/AA ratio and ACS occurrence were found to be significantly associated in patients without a smoking history; however, no such association existed in patients with a smoking history.

Hepatic lipogenesis is nutritionally regulated (i.e., downregulated during fasting and upregulated during the postprandial state) as an adaptation to the nutritional environment. While alterations in the expression level of the transcription factor SREBP-1c are known to be critical for nutritionally regulated lipogenesis, upstream mechanisms governing Srebf1 expression remain unclear. Here, we show that the fasting-induced transcription factor KLF15, a key regulator of gluconeogenesis, forms a complex with LXR/RXR, specifically on the Srebf1 promoter. This complex recruits the corepressor RIP140 instead of the coactivator SRC1, resulting in reduced Srebf1 and thus downstream lipogenic enzyme expression during the early and euglycemic period of fasting prior to hypoglycemia and PKA activation. Through this mechanism, KLF15 overexpression specifically ameliorates hypertriglyceridemia without affecting LXR-mediated cholesterol metabolism. These findings reveal a key molecular link between glucose and lipid metabolism and have therapeutic implications for the treatment of hyperlipidemia.

Migration to the inflamed tissue demands energy production in an increasingly hypoxic environment. Here the authors show that during migration, HIF1α-induced PDK1 uniquely adapts macrophage metabolism to mild hypoxia by promoting glycolysis while preserving cytochrome c oxidase activity.

Background Although an “obesity paradox” exists in patients after myocardial infarction, the association between obesity and the risk of sudden cardiac death (SCD) is limited. The aim of this study was to determine whether obesity is associated with an increased risk of SCD in Japanese survivors of acute myocardial infarction. Methods and Results Pooled data from 2 cohort studies in Japan, JCAD (Japanese Coronary Artery Disease) study and the Heart Institute of Japan Acute Myocardial Infarction‐II (HIJAMI‐II) registry, comprising of 6216 patients (mean age 65±11 years, 75.2% male) with acute myocardial infarction who were discharged alive, were studied. The patients were categorized into the following body mass index (BMI) groups at baseline according to the World Health Organization classification for Asian populations: BMI

Background: Cardiac resynchronization therapy is an effective device therapy for heart failure patients with conduction block. However, a problem with this invasive technique is the nearly 30% of non-responders. A number of studies have reported a functional line of block of cardiac excitation propagation in responders. However, this can only be detected using non-contact endocardial mapping. Further, although the line of block is considered a sign of responders to therapy, the mechanism remains unclear.Methods: Herein, we created two patient-specific heart models with conduction block and simulated the propagation of excitation based on a cellmodel of electrophysiology. In one model with a relatively narrow QRS width (176 ms), we modeled the Purkinje network using a thin endocardial layer with rapid conduction. To reproduce a wider QRS complex (200 ms) in the second model, we eliminated the Purkinje network, and we simulated the endocardial mapping by solving the inverse problem according to the actual mapping system.Results: We successfully observed the line of block using non-contact mapping in the model without the rapid propagation of excitation through the Purkinje network, although the excitation in the wall propagated smoothly. This model of slow conduction also reproduced the characteristic properties of the line of block, including dense isochronal lines and fractionated local electrocardiograms. Further, simulation of ventricular pacing from the lateral wall shifted the location of the line of block. By contrast, in the model with the Purkinje network, propagation of excitation in the endocardial map faithfully followed the actual propagation in the wall, without showing the line of block. Finally, switching the mode of propagation between the two models completely reversed these findings.Conclusions: Our simulation data suggest that the absence of rapid propagation of excitation through the Purkinje network is the major cause of the functional line of block recorded by non-contact endocardial mapping. The line of block can be used to identify responders as these patients loose rapid propagation through the Purkinje network.

To determine the involvement of sympathetic activity in choroidal neovascularization (CNV) using laser-induced CNV in a mouse model.We investigated changes in the proportions of intraocular lymphocytes, granulocytes, and three macrophage subtypes (Ly6Chi, Ly6Cint, and Ly6Clo) after laser injury in mice using flow cytometry, and evaluated CNV lesion size in mice lacking inflammatory cells. Further, we evaluated the lesion size in mice administered the β3 receptor antagonist, splenic-denervated and splenectomized mice. We also assessed changes in the proportions of intraocular macrophages and peripheral blood monocytes in splenic-denervated and splenectomized mice. Lastly, lesion size was compared between splenic-denervated mice with or without adoptive transfer of macrophages following laser injury. After Ly5.1 mice spleen-derived Ly6Chi cells were transferred into Ly5.2 mice, the proportions of intraocular Ly5.1+Ly6Chi cells were compared.In WT mice, the proportion of CD4+ T cells recruited into the eye increased progressively from day 3 to day 7 after laser injury, whereas, intraocular CD8+ T cells did not change significantly. Proportions of B220+ cells, granulocytes, and two subtypes of intraocular macrophages (Ly6Chi and Ly6Clo) peaked at day 3 following laser injury. In contrast, Ly6Cint/loCD64+ subtype showed a significantly higher percentage at day 7 after laser injury. There were no differences in lesion size between CD4-/-or Rag2-/-mice and controls, whereas lesion size was significantly reduced in CCR2-/- mice and clodronate liposome-treated mice. CNV lesion area was significantly reduced in mice with β3 blocker treatment, splenic-denervated and splenectomized mice compared with controls. Intraocular Ly6Chi macrophages were also reduced by splenic denervation or splenectomy. Adoptive transfer of spleen-derived Ly6Chi cells increased the lesion size in splenic-denervated mice. Compared with controls, intraocular donor-derived Ly6Chi cells recruited into the eye were reduced in splenic-denervated and splenectomized mice.Although lymphocytes had little effect on CNV formation, Ly6Chi macrophages/monocytes exacerbated CNV in mice. Sympathetic activity might contribute to CNV via the recruitment of macrophages to the eye.