Otsuka K, Takenaka S, Nagai T
… +16 more, Sato T, Konishi T, Tada A, Hamaya T, Mori Y, Takahashi A, Sasaki S, Tamano K, Tamura T, Kazui S, Yasui Y, Kobayashi Y, Temma T, Kamiya K, Wakasa S, Anzai T
BACKGROUND: The association of the lipid-core burden index (LCBI), measured using near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS), with early progression of cardiac allograft vasculopathy remains unclear....BACKGROUND: The association of the lipid-core burden index (LCBI), measured using near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS), with early progression of cardiac allograft vasculopathy remains unclear. METHODS AND RESULTS: We prospectively examined 12 consecutive heart transplant recipients who underwent NIRS-IVUS and IVUS. Patients were stratified according to the median maximum LCBI in a 4-mm segment (maxLCBI) of 223 at 1 month. The magnitude of maximal intimal thickness (MIT) progression was greater in the higher maxLCBIgroup. CONCLUSIONS: Patients with a higher maxLCBIat baseline exhibited greater MIT progression during the first post-transplant year.
BACKGROUND: Because vascular regeneration of diabetic lower limb ischemia (LLI) and prevention of disease progression is a major problem, we explored the molecular mechanism of E2F transcription factor 5 (E2F5) in regula...BACKGROUND: Because vascular regeneration of diabetic lower limb ischemia (LLI) and prevention of disease progression is a major problem, we explored the molecular mechanism of E2F transcription factor 5 (E2F5) in regulating autophagy to promote angiogenesis in diabetic HLI. METHODS AND RESULTS: The streptozotocin-induced diabetic mice model, hindlimb ischemia (HLI) model and high glucose (HG)-induced human umbilical vein endothelial cells (HUVECs) were constructed for in vivo and in vitro assays. Autophagy inhibitor, 3-methyladenine, reversed the effects of E2F5 overexpression on microtubule-associated protein 1 light chain 3B (LC3B) expression, cell proliferation, migration and tube formation, supporting the involvement of autophagy in E2F5-mediated HUVEC restoration. In vivo injection of E2F5 overexpressed lentivirus also promoted angiogenesis in diabetic HLI mice, concomitant with autophagy activation. Phosphorylated yes-associated protein (pYAP) expression in HUVECs was upregulated after HG treatment and E2F5 overexpression reversed this change. pYAP colocalized with CD31, and pYAP expression was decreased after E2F5 overexpression. Treatment with Ki16425 increased pYAP expression and affected the influence of E2F5 on the proliferation, migration and tubule formation of HUVECs, and LC3B expression. CONCLUSIONS: E2F5 promoted angiogenesis by downregulating pYAP, which is associated with autophagy activation. These findings provide a novel therapeutic strategy for diabetic LLI.
BACKGROUND: Although ventricular-arterial coupling (VAC) and C-reactive protein (CRP) are associated with the pathogenesis of heart failure (HF), their association in patients at risk of HF remains unclear. METHODS AND R...BACKGROUND: Although ventricular-arterial coupling (VAC) and C-reactive protein (CRP) are associated with the pathogenesis of heart failure (HF), their association in patients at risk of HF remains unclear. METHODS AND RESULTS: VAC was assessed by arterial elastance (Ea) to left ventricular endsystolic elastance (Ees) ratio (Ea/Ees) using the noninvasive single-beat method in 112 hypertensive patients. Log-transformed high-sensitivity CRP (hs-CRP) and categorical hs-CRP were associated with Ea/Ees on univariate analysis. Categorical hs-CRP was independently associated with Ea/Ees after adjusting for atherosclerotic risk factors, cardiac function and vascular function (β=0.27, P=0.003). CONCLUSIONS: hs-CRP was independently associated with VAC assessed by Ea/Ees in patients at risk of HF.
BACKGROUND: The prevalence of patients with heart failure with preserved ejection fraction (HFpEF) who meet the insurance eligibility criteria in Japan for obesity treatment with the glucagon-like peptide-1 receptor agon...BACKGROUND: The prevalence of patients with heart failure with preserved ejection fraction (HFpEF) who meet the insurance eligibility criteria in Japan for obesity treatment with the glucagon-like peptide-1 receptor agonist (GLP-1RA), and the dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist (GIP/GLP-1RA) remains unclear. METHODS AND RESULTS: This subanalysis of the PARACLETE study included compensated ambulatory patients with HFpEF. Among the 3706 patients, 654 (17.6%) were eligible for GLP-1RA and GIP/GLP-1RA. Eligible patients had more severe symptoms despite higher prescription rates of HF-related medications. CONCLUSIONS: Among patients with HFpEF in Japan, 17.6% met the insurance eligibility criteria for obesity treatment with GLP-1RA and GIP/GLP-1RA.
BACKGROUND: The prognostic significance of non-sustained ventricular tachycardia (NSVT) in Japanese patients receiving implantable cardioverter defibrillators (ICDs) for primary prevention remains unclear. This study aim...BACKGROUND: The prognostic significance of non-sustained ventricular tachycardia (NSVT) in Japanese patients receiving implantable cardioverter defibrillators (ICDs) for primary prevention remains unclear. This study aimed to verify the prognostic value of NSVT as recommended in the 2018 Japanese Circulation Society guideline. METHODS AND RESULTS: We analyzed 638 patients with structural heart disease who received an ICD or cardiac resynchronization therapy with defibrillator for primary prevention in the Nippon Storm Study. Analysis 1 (n=429) evaluated the association between NSVT history and predefined endpoints in patients with ischemic heart disease (IHD) or non-ischemic heart disease (non-IHD) and reduced left ventricular ejection fraction. Analysis 2 (n=357) assessed the prognostic impact of NSVT documented by Holter electrocardiography across 2 subgroups: Subgroup 1, IHD and non-IHD; and Subgroup 2, other cardiac diagnoses. Endpoints included appropriate ICD therapy, electrical storm, ventricular fibrillation (VF), shock therapy, and mortality. In Analysis 1, a history of NSVT was not significantly associated with appropriate ICD therapy or other major adverse outcomes. In Analysis 2, Holter-documented NSVT was independently associated only with appropriate ICD therapy (hazard ratio [HR] 1.82; 95% confidence interval 1.04-3.18; P=0.035). This association was significant in Subgroup 2, but not in Subgroup 1. CONCLUSIONS: NSVT was modestly associated (HR 1.82) with appropriate ICD therapy but not with VF or mortality, suggesting reconsideration of its clinical role.
BACKGROUND: The optimal timing for lactate sampling during acetylcholine (ACh) provocation to detect metabolic ischemia remains unclear. METHODS AND RESULTS: In 20 patients with suspected INOCA, blood samples from the co...BACKGROUND: The optimal timing for lactate sampling during acetylcholine (ACh) provocation to detect metabolic ischemia remains unclear. METHODS AND RESULTS: In 20 patients with suspected INOCA, blood samples from the coronary artery and coronary sinus were obtained at baseline, every minute for 5 min after ACh, and after nitroglycerin. Metabolic ischemia (negative lactate extraction ratio) occurred in 12 patients: 10 patients exhibited ischemia at 1 min, and 2 patients only at 2 min. No ischemia was observed beyond 3 min. CONCLUSIONS: Sampling at both 1 and 2 min may reduce false-negative detection of metabolic ischemia during ACh provocation.
BACKGROUND: The optimal treatment for functionally insignificant intermediate stenosis in non-infarct-related artery (IRA) after acute myocardial infarction (AMI) remains controversial. We identified high-risk non-IRAs u...BACKGROUND: The optimal treatment for functionally insignificant intermediate stenosis in non-infarct-related artery (IRA) after acute myocardial infarction (AMI) remains controversial. We identified high-risk non-IRAs using quantitative flow ratio (QFR)-derived physiological indices and evaluated their prognostic and therapeutic implications. METHODS AND RESULTS: We retrospectively assessed QFR-derived physiology in 240 non-IRAs (189 deferred [Defer group], 51 treated [percutaneous coronary intervention (PCI) group]) with diameter stenosis ≥40% and QFR ≥0.8 in 205 AMI patients treated between January 2014 and December 2023. In the Defer group, physiological indices associated with target vessel failure (TVF) were identified, and their discriminative performance and optimal cut-off values were determined using time-dependent receiver operating characteristic curve analysis with the Youden index. Adding QFR pressure pullback gradient (PPG) to QFR significantly enhanced time-dependent risk reclassification, as reflected by net reclassification improvement (P=0.039) and integrated discrimination improvement (P=0.023). After stratification using Youden-derived 3-year optimal cut-off values of 0.88 for QFR and 0.78 for QFR-PPG, deferred non-IRAs with high-risk physiology (QFR <0.88 and QFR-PPG <0.78) had a significantly higher 3-year TVF rate than those without high-risk physiology (42.1% vs. 9.9%; P<0.001). Among high-risk non-IRAs, the TVF rate was significantly higher in the Defer than PCI group, whereas it was similar among non-IRAs without high-risk physiology (P for interaction=0.040). CONCLUSIONS: QFR-derived physiology, including QFR and QFR-PPG, can stratify high-risk non-IRAs and guide optimal treatment in patients with AMI.
BACKGROUND: Despite intensive control of established coronary risk factors, such as dyslipidemia, hypertension, and diabetes, cardiovascular events continue to occur in high-risk patients. Residual risk attributable to c...BACKGROUND: Despite intensive control of established coronary risk factors, such as dyslipidemia, hypertension, and diabetes, cardiovascular events continue to occur in high-risk patients. Residual risk attributable to chronic low-grade inflammation has therefore emerged as a major clinical concern. METHODS AND RESULTS: This narrative review summarizes current evidence regarding the role of low-intensity chronic inflammation in cardiovascular disease risk, based on literature searches of PubMed. Randomized controlled trials targeting inflammation, including Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), Colchicine Cardiovascular Outcomes Trial (COLCOT), and Low-Dose Colchicine 2 Trial (LoDoCo2), demonstrated that suppression of chronic inflammation reduces cardiovascular disease events independently of low-density lipoprotein cholesterol levels. In addition, evidence from randomized trials, observational studies, and systematic reviews supports the clinical value of high-sensitivity C-reactive protein for identifying residual inflammatory risk, including in Japanese patients at high cardiovascular risk. CONCLUSIONS: High-sensitivity C-reactive protein is a practical and reliable biomarker for assessing low-grade chronic inflammation. Therapeutic strategies targeting inflammation are as important as lipid-lowering interventions and represent a promising approach for reducing residual cardiovascular risk.
BACKGROUND: Previous clinical studies reported that testosterone replacement therapy unexpectedly increased cardiovascular (CV) events in elderly men, through an unknown underlying mechanism. Because nitric oxide (NO) pr...BACKGROUND: Previous clinical studies reported that testosterone replacement therapy unexpectedly increased cardiovascular (CV) events in elderly men, through an unknown underlying mechanism. Because nitric oxide (NO) production is reduced in elderly men, we hypothesized that testosterone exerts harmful CV effects under reduced NO production, and examined this hypothesis using a 2/3 nephrectomized triple neuronal/inducible/endothelial NO synthases (NOS)-knockout (NX-TKO) mouse model that causes death from myocardial infarction (MI). METHODS AND RESULTS: The survival rate was markedly worse in male NX-TKO mice than in male NX-wild-type (NX-WT) mice. Orchiectomy (ORX) significantly aggravated the survival rate in NX-WT mice, but significantly improved it in NX-TKO mice. In the NX-TKO-ORX mice, long-term subcutaneous treatment with testosterone significantly deteriorated the survival rate, the incidence of MI, and CV risk factors. Furthermore, testosterone-induced aortic relaxations were significantly more impaired in the TKO than in the WT mice. RNA sequencing in the hearts of TKO-ORX mice without and with testosterone treatment indicated possible involvements of immunity- and inflammation-mediated mechanisms in the harmful CV effects of testosterone. CONCLUSIONS: These results provide the first evidence that testosterone exerts harmful CV effects, including shorter survival, increased incidence of MI, impaired arterial relaxation, and exacerbated cardiovascular risk factors, in the absence of NOS in mice. Our findings may explain in part why testosterone replacement therapy increases CV events in elderly men.
Okuno Y, Hanatani S, Ogata F
… +12 more, Yamaguchi S, Yamamoto M, Kuyama N, Ishii M, Usuku H, Yamamoto E, Oda S, Izumiya Y, Soejima H, Kawano H, Hirai T, Tsujita K
BACKGROUND: Human epididymis protein 4 (HE4) is a novel fibrosis marker expressed in activated myofibroblasts. Although we previously demonstrated its prognostic value in dilated cardiomyopathy, its significance in gener...BACKGROUND: Human epididymis protein 4 (HE4) is a novel fibrosis marker expressed in activated myofibroblasts. Although we previously demonstrated its prognostic value in dilated cardiomyopathy, its significance in general heart failure with reduced ejection fraction (HFrEF) remains unclear. METHODS AND RESULTS: Serum HE4 concentrations were measured in 140 patients with HFrEF (left ventricular ejection fraction <40%) and followed for up to 3 years to assess cardiovascular (CV) death and heart failure hospitalization. Kaplan-Meier analysis revealed significantly higher CV event rates in the high HE4 group (above the median) than in the low HE4 group (log-rank P<0.001). Multivariate Cox regression analysis identified HE4 (ln[HE4]) as an independent predictor of adverse outcomes (hazard ratio 3.99; 95% confidence interval [CI] 2.05-7.75; P<0.001). In multivariate linear regression, HE4 was significantly associated with age, serum creatinine, plasma B-type natriuretic peptide, E/e', and global longitudinal strain (GLS; β=-0.083; 95% CI -0.111, -0.054; P<0.001). Combining HE4 and GLS demonstrated that patients with high HE4 and low GLS had the highest CV event rate (log-rank P<0.001). CONCLUSIONS: HE4 is an independent prognostic biomarker in HFrEF, and its association with GLS may reflect underlying myocardial dysfunction and fibrotic remodeling leading to adverse outcomes.
BACKGROUND: We investigated associations between the low-density lipoprotein cholesterol (LDL-C) to high-density lipoprotein cholesterol (HDL-C) ratio (L/H ratio) and cardiovascular events in high-risk type 2 diabetes (T...BACKGROUND: We investigated associations between the low-density lipoprotein cholesterol (LDL-C) to high-density lipoprotein cholesterol (HDL-C) ratio (L/H ratio) and cardiovascular events in high-risk type 2 diabetes (T2D) patients with diabetic retinopathy receiving statins. METHODS AND RESULTS: We conducted a post hoc analysis of the EMPATHY study, a randomized controlled trial comparing intensive vs. standard statin therapy in T2D patients with retinopathy and hypercholesterolemia without cardiovascular disease. Baseline and 12-month (12M) L/H ratios were assessed as single and serial measures. Baseline data were available for 5,006 patients (median L/H ratio 2.016), categorized as having either a high (≥2.0) or low (<2.0) L/H ratio. Over a median 36.8-month follow-up, 184 cardiovascular events occurred. The risk of cardiovascular events was higher in the group with a high than low L/H ratio, even after adjusting for age, sex, and LDL-C (hazard ratio 1.89; 95% confidence interval 1.31-2.73; P<0.001); 12M L/H ratio analysis yielded similar results. In serial categories, both low-high (baseline <2.0; 12M ≥2.0) and high-high (baseline ≥2.0; 12M ≥2.0) groups had higher risk than the low-low group (baseline <2.0; 12M <2.0). No significant interactions were observed by age, sex, LDL-C, HDL-C, or statin intensity. CONCLUSIONS: An L/H ratio ≥2.0 identifies increased cardiovascular risk in statin-treated T2D patients with diabetic retinopathy and hypercholesterolemia without prior cardiovascular disease. Serial L/H ratio assessment may aid risk stratification in this high-risk population.
Suzuki K, Takaoka H, Ota M
… +13 more, Ishio N, Shikama N, Noguchi Y, Kinoshita M, Aoki S, Matsumoto M, Yashima S, Kanda T, Sasaki H, Suzuki-Eguchi N, Kato K, Matsumiya G, Kobayashi Y
BACKGROUND: Changes in N-terminal pro B-type natriuretic peptide (NT-proBNP) levels and cardiac remodeling from baseline to follow-up in patients with heart failure with reduced ejection fraction (HFrEF) treated with ver...BACKGROUND: Changes in N-terminal pro B-type natriuretic peptide (NT-proBNP) levels and cardiac remodeling from baseline to follow-up in patients with heart failure with reduced ejection fraction (HFrEF) treated with vericiguat remain unclear. METHODS AND RESULTS: The VERIFY-HF registry is a nationwide multicenter retrospective single-arm study of patients with HFrEF newly prescribed vericiguat at 22 hospitals in Japan. In this study, we analyzed baseline and follow-up echocardiography findings of 504 patients. Vericiguat dose-dependently reduced NT-proBNP levels, with a greater reduction in those receiving 7.5 or 10 than ≤5 mg vericiguat (NT-proBNP least-squares geometric mean ratio [3 months/baseline] 0.53 vs. 0.65, respectively; P=0.009). Multivariable analysis revealed that high-dose (7.5 or 10 mg) vericiguat was independently associated with a greater reduction in log-transformed NT-proBNP at 3 months (β=-0.125; 95% confidence interval [CI] -0.247, -0.004; P=0.043). High-dose vericiguat was not significantly associated with changes in left ventricular ejection fraction (LVEF) at 12 months (β=0.53; 95% CI -0.49, 1.6; P=0.30). Overall, reverse remodeling at 12 months was modest (LVEF, +4.7%; left ventricular end-systolic volume index, -6.4 mL/m) and was predominantly associated with newly initiated β-blockers or renin-angiotensin system inhibitors within 3 months prior to vericiguat administration or prior heart failure hospitalization rather than vericiguat dose. CONCLUSIONS: In this real-world registry study, high-dose vericiguat was associated with sustained dose-dependent reductions in NT-proBNP, but not cardiac reverse remodeling.
Taniguchi M, Taruya A, Kitahara C
… +20 more, Ota S, Kato T, Desaki Y, Sasaki I, Katayama Y, Wada T, Takahata M, Satogami K, Ozaki Y, Kashiwagi M, Shiono Y, Honda K, Yamano T, Takemoto K, Kuroi A, Kitabata H, Hemmi H, Matsuoka T, Nishimura Y, Tanaka A
BACKGROUND: Visceral fat (VF), particularly epicardial adipose tissue (EAT), plays a crucial role in the development of coronary artery disease (CAD). Cathelicidin (LL37) is an antimicrobial peptide involved in innate im...BACKGROUND: Visceral fat (VF), particularly epicardial adipose tissue (EAT), plays a crucial role in the development of coronary artery disease (CAD). Cathelicidin (LL37) is an antimicrobial peptide involved in innate immunity and has been implicated in inflammatory processes. However, the relationship between VF accumulation, cathelicidin, and atherosclerosis remains unclear. METHODS AND RESULTS: Seventy-eight subjects without CAD were enrolled and classified by obesity type: normal-weight (normal; n=20), subcutaneous fat (SF; n=19), and VF (n=39). Plasma LL37 concentrations were compared across groups. LL37 expression in EAT was assessed in 9 patients undergoing open-heart surgery, stratified by CAD status. In animal experiments, angiotensin II-infused wild-type and Apoemice fed a Western-type diet were treated with cathelicidin-related antimicrobial peptide (CRAMP) small interfering RNA (siRNA), scrambled siRNA, or vehicle. Atherosclerotic lesions were evaluated by enface Sudan IV staining. Plasma LL37 concentrations were higher in the VF than in the normal-weight and SF groups (median [IQR] 99.11 [91.70-129.86] vs. 58.63 [50.03-70.05] and 69.81 [54.64-87.39] ng/mL, respectively; P<0.001) and were correlated with VF area and EAT volume. LL37 expression in EAT was higher in patients with than without CAD (2.34 [2.06-3.90] % vs. 1.34 [0.81-1.49] %; P=0.034). Treatment with CRAMP siRNA significantly reduced atherosclerotic lesion area in Apoemice without affecting blood pressure or lipid profiles. CONCLUSIONS: LL37 is associated with VF accumulation and CAD. However, these findings are exploratory and warrant prospective validation to determine its potential utility as a biomarker.
BACKGROUND: The 2025 Asian Working Group for Sarcopenia (AWGS) updated diagnostic criteria redefine sarcopenia based on low muscle strength and low skeletal muscle mass, incorporating body mass index (BMI)-adjusted appen...BACKGROUND: The 2025 Asian Working Group for Sarcopenia (AWGS) updated diagnostic criteria redefine sarcopenia based on low muscle strength and low skeletal muscle mass, incorporating body mass index (BMI)-adjusted appendicular skeletal muscle mass (ASM) alongside height-adjusted ASM. The clinical relevance of these definitions in heart failure (HF) patients remains unclear. METHODS AND RESULTS: This retrospective study included 594 patients aged ≥65 years hospitalized for HF (2016-2024). Sarcopenia was defined according to AWGS 2025 criteria as H-sarcopenia (height-adjusted ASM) or B-sarcopenia (BMI-adjusted ASM). The primary outcome was all-cause mortality. Physical function was assessed using gait speed. We analyzed associations using Cox proportional hazards and linear regression models. The prevalence of H-sarcopenia and B-sarcopenia was similar (24.2% vs. 25.1%, respectively), but BMI-dependent patterns differed, with the prevalence of H-sarcopenia decreasing and B-sarcopenia increasing as BMI increased. H-sarcopenia was independently associated with higher mortality (adjusted hazard ratio 1.48; 95% confidence interval 1.04-2.12), although its prognostic impact was attenuated at higher BMI. B-sarcopenia was not associated with mortality. Both sarcopenia definitions were associated with slower gait speed (P<0.001), but B-sarcopenia showed superior model performance (P<0.001 for the difference in root mean square error). CONCLUSIONS: In patients hospitalized with HF, H-sarcopenia and B-sarcopenia had distinct prognostic and functional implications: H-sarcopenia was related to mortality, particularly for lower BMI, whereas B-sarcopenia better reflected physical function, supporting outcome-specific sarcopenia definitions.
BACKGROUND: Peripartum cardiomyopathy (PPCM) is a potentially life-threatening condition. The histological characteristics of PPCM as risk factors for poor outcomes have not been thoroughly investigated. This study evalu...BACKGROUND: Peripartum cardiomyopathy (PPCM) is a potentially life-threatening condition. The histological characteristics of PPCM as risk factors for poor outcomes have not been thoroughly investigated. This study evaluated the pathological findings of PPCM, with a particular focus on inflammatory factors such as tenascin-C (TNC) and interleukin-6, which may predict left ventricular dysfunction and the prognosis of PPCM. METHODS AND RESULTS: We conducted a retrospective single-center observational study involving endomyocardial biopsies (from 27 patients) as clinically diagnosed PPCM. We assessed the association between the histology and cardiac events, namely cardiac death, left ventricular assist device implantation, and/or heart transplantation. During the median follow-up period of 2,100 days, 7 (25.9%) composite events were documented. Kaplan-Meier survival curves demonstrated that patients with advanced cardiac fibrosis had significantly poorer long-term outcomes than those with mild cardiac fibrosis (log-rank P=0.0003). Furthermore, TNC-positive patients with advanced fibrosis had significantly worse event-free survival than TNC-negative patients with advanced fibrosis and patients with mild fibrosis (Bonferroni-adjusted P=0.016 and P<0.0001, respectively). Interleukin-6 expression was higher in cardiac tissue from PPCM patients who were TNC positive (P=0.03). CONCLUSIONS: Cardiac histopathology in PPCM patients can predict long-term prognosis; both advanced fibrosis and immunohistochemical TNC expression are associated with poor prognosis.