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Transplant recipients (TRs) are at high risk for severe coronavirus disease 2019 (COVID-19). Neutralizing monoclonal antibodies (mAbs) are used for treating mild-to-moderate COVID-19. However, reports comparing the efficacy of COVID-19 treatment without/with mAbs in TRs are limited. We assessed the efficacy of casirivimab/imdevimab against mild-to-moderate COVID-19 in TRs.Forty-one patients were retrospectively evaluated. The duration until defervescence, oxygen (OCasirivimab/imdevimab was correlated with shorter duration until defervescence and non-requirement of OCasirivimab/imdevimab was effective and increased the neutralizing antibody in TRs with mild-to-moderate COVID-19, it may contribute toward preventing the progression.

Hospital-acquired severe acute respiratory virus coronavirus 2 (SARS-CoV-2) infection is a healthcare challenge. We hypothesized that polymerase chain reaction testing of symptomatic triaged outpatients and all inpatients before hospitalization in Shinjuku, a coronavirus disease 2019 (COVID-19) epicenter in Tokyo, using the Tokyo Women's Medical University (TMWU) model would be feasible and efficient at preventing COVID-19. This retrospective study enrolled 2981 patients from March to May 2020. The prevalence of SARS-CoV-2 infection was 1.81% (95% credible interval [CI]: 0.95–3.47%) in triaged symptomatic outpatients, 0.04% (95% CI: 0.0002–0.2%) in scheduled asymptomatic inpatients, 3.78% (95% CI: 1.82–7.26%) in emergency inpatients, and 2.4% (95% CI: 1.49–3.82%) in symptomatic patients. There were no cases of hospital-acquired SARS-CoV-2 infection. This shows that the TWMU model could prevent hospital-acquired SARS-CoV-2 infection and is feasible and effective in reducing the impact of SARS-CoV-2 infection in the hospitals.

Left ventricular (LV) diastolic dysfunction is associated with heart failure with preserved ejection fraction, and metabolic syndrome (MetS) is a risk factor. However, there is limited knowledge regarding the metabolic factors that contribute to LV dysfunction in postmenopausal women without comorbidities. This study aimed to analyze the relationship between LV diastolic dysfunction and MetS, as well as other cardiovascular risk factors, and to determine risks for LV diastolic dysfunction. Postmenopausal women without hypertension, diabetes mellitus, LV systolic dysfunction, or other heart diseases underwent physical examinations, including echocardiography. The study participants were diagnosed with LV diastolic dysfunction based on several echocardiographic parameters. Logistic regression analyses of LV diastolic dysfunction and cardiovascular risk factors were performed. Of the 269 postmenopausal women examined, 29 (10.7%) and 40 (14.9%) had MetS and LV diastolic dysfunction, respectively. Abnormal diastolic blood pressure (odds ratio, 3.6; 95% confidence interval, 1.16-10.9; P 0.05) and age (odds ratio, 1.1; 95% confidence interval, 1.07-1.19; P 0.01) were predictors of LV diastolic dysfunction. In healthy postmenopausal women, high-normal diastolic blood pressure was the only independent risk factor for LV diastolic dysfunction, and it thus may be a useful predictor of diastolic heart failure during routine physical examinations.

Background: Solid organ transplant recipients (SOTRs) are at high risk for severe coronavirus disease 2019 (COVID-19) due to comorbidities and immunosuppression. Moreover, the treatment for COVID-19 is limited. Neutralizing monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 are used for treating mild-to-moderate COVID-19. However, reports comparing the efficacy of COVID-19 treatment with and without neutralizing mAbs in SOTRs are limited. Here, we assessed the efficacy of casirivimab/imdevimab as neutralizing mAbs against mild-to-moderate COVID-19 in SOTRs. Methods: Forty-one patients hospitalized from September 2020 to September 2021 at Tokyo Women’s Medical University Hospital were included. The duration until antifebrile and of hospitalization, requirement of oxygen (O2) ≥ 5 L, and neutralizing antibody levels were compared in SOTRs with COVID-19 who received and those who did not receive casirivimab/imdevimab therapy.Results: Casirivimab/imdevimab therapy correlated with less duration until antifebrile and of hospitalization and non-requirement of O2 ≥ 5 L in SOTRs with COVID-19 [mean days without vs. with casirivimab/imdevimab: 6 vs. 2; P = 0.0002, hazard ratio (HR) = 0.3333, 95% confidence interval (CI) = 0.1763–0.6301; mean days: 15 vs. 8; P < 0.0001, HR = 0.5333, 95% CI = 0.2878–0.9883; P = 0.0377, HR = 0.1502, 95% CI = 0.02511–0.8980, respectively]. Further, casirivimab/imdevimab therapy was associated with early antifebrile after adjusting for sex and age (P = 0.013, HR = 0.412, 95% CI = 0.205–0.826). Although no significant difference was observed in neutralizing antibody levels between patients without and with casirivimab/imdevimab therapy on the day of hospitalization (P = 0.1055), including 13 SOTRs who had received vaccination. Neutralizing antibody levels were higher in patients with casirivimab/imdevimab therapy at 3–5 days after hospitalization including such patients in whom the levels tended to stay lower despite vaccination than in those without casirivimab/imdevimab at 7–9 days after hospitalization (P < 0.0001, mean antibody without vs. with, 414.9 vs. 40000). Conclusion: Casirivimab/imdevimab therapy was effective and increased the neutralizing antibody levels in SOTRs with mild-to-moderate COVID-19. Therefore, casirivimab/imdevimab therapy could contribute to preventing the progression of mild-to-moderate COVID-19 in SOTRs.

Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection., 「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.

To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.

Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 has spread explosively throughout the world and has since been declared a pandemic by the World Health Organization. Although it is recommended that upper gastrointestinal endoscopies either be postponed or canceled during the pandemic because of their high risk of aerosol generation, this does not apply in emergency cases, which may include patients with coronavirus disease. In this case report, we describe the safe undertaking of an emergency upper gastrointestinal endoscopy in a patient with suspected hemorrhagic shock who tested positive for the severe acute respiratory syndrome coronavirus 2 using the polymerase chain reaction. We performed the procedure in the contamination zone of a specialized coronavirus disease ward with prespecified zones. Full personal protective equipment was worn during the procedure, as recommended by various academic societies, and careful attention was paid to the sterilization of all equipment after the procedure. Thus, emergency endoscopies can be performed safely in patients with coronavirus disease in a suitable environment by using appropriate personal protective equipment and by handling the equipment appropriately.

It was shown in a previous cohort study that men with internal carotid artery (ICA) plaque, defined as focal wall thickness of ≥ 1.5 mm, had a threefold higher risk of stroke than those without plaque. We examined the relationship between arousal indices and sleep stages in patients with obstructive sleep apnea syndrome (OSAS) and carotid atherosclerosis. Carotid atherosclerosis severity was evaluated using the maximal carotid wall intima-media thickness of the ICA (ICA-maxIMT) and plaque in 83 patients with OSAS. The ICA-maxIMT values were positively correlated with the apnea hypopnea index (AHI) (ρ = 0.294, P = 0.007), arousal index (ρ = 0.289, P = 0.008), oxygen desaturation index (ρ = 0.298, P = 0.006), percentage of visually scored total sleep time spent in nocturnal oxygen saturation

BACKGROUND The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial was conducted to compare the effects of regimens combining the dihydropyridine calcium-channel blocker benidipine with each of 3 secondary agent types (an angiotensin-receptor blocker (ARB), a β-blocker and a thiazide) in Japanese hypertensive outpatients who did not achieve target blood pressure (

Introduction Contrast-induced nephropathy is a complication following coronary angiography and percutaneous coronary intervention. Because contrast-induced nephropathy is a predictor of long-term mortality in patients with ischemic heart disease undergoing percutaneous coronary intervention, preventive strategies are required. We assessed the effects of periprocedural oxygenation on contrast-induced nephropathy among patients with pre-existing renal dysfunction. Methods A total of 200 consecutive patients with impaired renal function (estimated glomerular filtration < 60 ml/min per 1.73 m2) undergoing elective cardiovascular angiography were randomly assigned to an oxygenation treatment (n = 100) or control group (n = 100). In oxygenation treatment, pure oxygen (2 L/min) was administered for 10 minutes before exposure to contrast medium. The primary endpoint was the incidence of contrast-induced nephropathy, defined as a ≥ 25% increase in serum creatinine levels from baseline within 48 hours of exposure. Results In the oxygenation treatment group, partial pressure of arterial oxygen was higher (135 ± 25 mm Hg vs. 84 ± 10 mm Hg, P

Objective Plasma cancer antigen (CA)-125 is a tumour marker recently shown to be associated with systolic heart failure and new-onset atrial fibrillation (AF) after myocardial infarction. However, no reports have described the relationship between CA-125 and new-onset AF in healthy postmenopausal women. The aim of the present study was to evaluate the relationship between CA-125 and new-onset AF in postmenopausal women. Methods Between 2005 and 2015, 2086 women, including 1012 postmenopausal women, visited our hospital for annual health check-ups. We excluded patients with systolic dysfunction, chronic inflammatory disease, chronic obstructive pulmonary disease, histories of AF or neoplastic diseases. A total of 746 postmenopausal women underwent thorough physical examinations, including those for biomarkers such as brain natriuretic peptide, high-sensitivity C-reactive protein (hs-CRP) and CA-125. Results During the 10-year observation period, AF was documented in 31 participants (4.2%). The mean age of participants developing AF (75±6 years) was higher than that of those without AF (68±8 years). Participants developing AF showed significantly higher CA-125 (11.4±6.3 U/mL) and hs-CRP (0.10±0.11 mg/dL) levels than did those without AF (7.7±3.2 U/mL, p

Although some studies have attempted to find useful prognostic factors in hypertrophic cardiomyopathy (HCM), those results are not fully helpful for use in actual clinical practice. Furthermore, several genetic abnormalities associated with HCM have been identified. However, the genotype-phenotype correlation in HCM remains to be elucidated. Here, we attempted to assess patients with different types of gene mutations causing HCM and investigate the prognosis. A total of 140 patients with HCM underwent a screening test for myofilament gene mutations by direct sequencing of eight sarcomeric genes. Patients with a single mutation in cardiac troponin T, cardiac troponin I, α-tropomyosin, and regulatory and essential light chains were excluded from the study because the number of cases was too small. The clinical presentations and outcomes of the remaining 127 patients with HCM, 31 β-myosin heavy chain (MYH7) mutation carriers, 19 cardiac myosin-binding protein C (MYBPC3) mutation carriers, and 77 mutation non-carriers were analyzed retrospectively. MYBPC3 mutation carriers had a high frequency of ventricular arrhythmia and syncope. Kaplan-Meier curves revealed no significant difference in prognosis among the three groups, but a lack of family history of sudden death (SD) and a past history of syncope were significantly related to poor prognosis. An absence of family history of SD and past history of syncope are useful prognostic factors in patients with HCM. MYH7 and MYBPC3 mutations did not significantly influence prognosis compared to non-carriers. However, patients with the MYBPC3 mutation should be closely followed for the possibility of SD.

Background Serelaxin, a recombinant form of human relaxin-2, is in development for treating acute heart failure (AHF) and a Phase II study in Japanese AHF patients was conducted. Methods and results A randomized, double-blind, placebo-controlled study of serelaxin at 10 and 30 µg·kg(-1)·day(-1)continuous intravenous infusion for up to 48 h, added to standard care for Japanese AHF patients. Primary endpoints were adverse events (AEs) through Day 5, serious AEs (SAEs) through Day 14, and serelaxin pharmacokinetics. Secondary endpoints included changes in systolic blood pressure (SBP) and cardiorenal biomarkers. A total of 46 patients received the study drug and were followed for 60 days. The observed AE profile was comparable between the groups, with no AEs of concern. Dose-dependent increase in the serum concentration of serelaxin was observed across the 2 dose rates of serelaxin. A greater reduction in SBP was observed with serelaxin 30 µg·kg(-1)·day(-1)vs. placebo (-7.7 [-16.4, 1.0] mmHg). A greater reduction in NT-proBNP was noted with serelaxin (-50.8% and -54.9% for 10 and 30 µg·kg(-1)·day(-1), respectively at Day 2). Conclusions Serelaxin was well tolerated in this study with Japanese AHF patients, with no AEs of concern and favorable beneficial trends on efficacy. These findings support further evaluation of serelaxin 30 µg·kg(-1)·day(-1)in this patient population.

Objective To determine whether adequate myocardial perfusion status after transluminal recanalization is associated with prompt improvement of QT dispersion (QTd). Background Transluminal recanalization of the infarct-related coronary artery in acute myocardial infarction aims to promptly restore myocardial perfusion, to maximize electrical and mechanical recovery. QTd represents the heterogeneity of ventricular repolarization, which may affect electrical stability. Methods Forty patients who underwent primary percutaneous coronary intervention for their first anterior acute ST-elevation myocardial infarction were prospectively enrolled. Myocardial reperfusion status was assessed by myocardial blush grade (MBG) on the final angiogram after successful recanalization (Thrombolysis In Myocardial Infarction Grade 3 flow). Results Preprocedural QTd was similar in patients with final MBG 0–1, 2, and 3 (76 ± 24, 67 ± 13, and 69 ± 13 milliseconds, respectively; P = 0.661). After recanalization, QTd decreased in patients with MBG 3 (39 ± 16 milliseconds, P

PURPOSE: Cardiac involvement is an important prognostic factor in sarcoidosis, and cardiovascular magnetic resonance (CMR) imaging with late gadolinium enhancement (LGE) can facilitate the identification of cardiac sarcoidosis (CS). In patients with CS, we investigated LGE characteristics and their relationship with left ventricular (LV) function to identify those characteristics unique to severely reduced LV function. We also investigated the relationship between LGE and duration of sarcoidosis. MATERIALS AND METHODS: We retrospectively evaluated 19 patients with CS diagnosed according to the 2006 revised guidelines of the Japanese Ministry of Health and Welfare who underwent CMR imaging. We analyzed LGE location using 17-segment and subsegment (subepicardial, midwall, subendocardial, and transmural) models and evaluated the relationship between the characteristics of LGE and LV ejection fraction (LVEF) and duration of sarcoidosis. RESULTS: Images of 17 of the 19 patients showed LGE most frequently in the subepicardial layer. The total number of affected segments with LGE correlated significantly with LVEF (r=-0.84, P

Neural stem cells (NSCs) differentiate into endothelial cells (ECs) and neuronal cells. Estradiol (E2) is known to exhibit proangiogenic effects on ischemic tissues via EC activation. Therefore, we hypothesized that E2 can promote the therapeutic potential of NSC transplantation for injured nerve repair via the differentiation of NSCs into ECs during neovascularization. NSCs isolated from newborn mouse brains were transplanted into injured sciatic nerves with (NSC/E2 group) or without E2-conjugated gelatin hydrogel (E2 group). The NSC/E2 group exhibited the greatest recovery in motor nerve conduction velocity, voltage amplitude, and exercise tolerance. Histological analyses revealed increased intraneural vascularity and blood perfusion as well as striking NSC recruitment to the neovasculature in the injured nerves in the NSC/E2 group. In vitro, E2 enhanced the NSC migration and proliferation inhibiting apoptosis. Fluorescence-activated cell sorting analysis also revealed that E2 significantly increased the percentage of CD31 in NSCs, and the effect of E2 was completely neutralized by the estrogen receptor antagonist ICI. The combination of E2 administration and NSC transplantation cooperatively improved the functional recovery of injured peripheral nerves, at least in part, via E2-associated NSC differentiation into ECs. These findings provide a novel mechanistic insight into both NSC biology and the biological effects of endogenous E2.

The aim of this study was to assess the effects of angiotensin receptor blocker (ARB)-based therapy on cardiovascular events in high-risk hypertensive patients with coronary artery disease (CAD) and impaired renal function in post hoc analysis of HIJ-CREATE (Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease). Patients (n=2049) were randomly assigned to candesartan-based or non-ARB treatment arms; 1022 patients (age 70 ± 6 years, 28% female) with impaired renal function, defined as creatinine clearance

It remains unclear whether the combination of dual-chamber (DDD) pacing and disopyramide can achieve prolonged left ventricular outflow tract (LVOT) gradient reduction and symptom relief in patients with obstructive hypertrophic cardiomyopathy (HCM). In an HCM patient with a severe LVOT gradient, the combination of DDD pacing and disopyramide achieved marked improvement of gradient in the catheter laboratory and also after medium-term follow-up. The patient's severe dyspnoea was alleviated during the follow-up period. This combination might enable physicians to treat and manage elderly symptomatic obstructive HCM patients with a severe LVOT gradient more effectively and less invasively.

Objectives and background Recent evidence has revealed that aldosterone (ALDO) is produced in the vasculature, and acts directly in the cardiovascular system. This study was designed to examine the role of ALDO in the process of long-term renin–angiotensin system (RAS) induced vascular remodeling. Material and method Hypertensive transgenic mice that overproduce angiotensin II (AngII), i.e., Tsukuba-Hypertensive-Mice (THM), were given tap water or 1% salt water and treated with or without Spironolactone (SPRL: 20 mg/kg/day) for 4 weeks. We also employed A7r5 cells and investigated the effect of SPRL on the AngII mediated signal transduction in the vascular smooth muscle cells. Results Intimal hyperplasia, medial hypertrophy and degradation of medial elastic laminae were observed in the abdominal aorta, independent of blood pressure. Taking 1% salt water markedly enhanced these changes. In contrast, SPRL-treated THM showed almost complete disappearance of these intimal hyperplasia and medial hypertrophy. Osteopontin (OPN) was markedly up-regulated in the intima and media. However, it was inhibited by SPRL treatment in spite of high level of AngII. In A7r5 cells, AngII (10 −7 μM) induced OPN expression and pretreatment with MEK, PI3K, and EGFR inhibitor suppressed it. SPRL pretreatment also inhibited AngII-induced ERK and AKT phosphorylation, and resulted in the suppression of AngII-induced OPN expression. Conclusions ALDO blockade by SPRL restores the vascular remodeling caused by the long-term RAS enhancement even in the high level of AngII, independent of blood pressure. Blocking AngII alone may not be sufficient, and direct ALDO blockade is also important to prevent vascular disease.

The extracellular matrix (ECM) acts as a critical factor during morphogenesis. Because the organization of the ECM directly influences the structure of tissues and organs, a determination of the way that ECM organization is regulated should help to clarify morphogenesis. We have analyzed the assembly of Del1, an ECM protein produced by endothelial cells in embryos, in the ECM. Del1 consists of three epidermal growth factor repeats (E1-E3) at its N-terminus and two discoidin domains (C1, C2) at its C-terminus. Experiments with various deletion mutants of Del1 have revealed that fragments containing the C-terminus of C1, which has a lectin-like structure, direct deposition in the ECM. The efficiency of deposition varies according to the presence of other domains in Del1. A fragment containing E3 and C1 has the strongest deposition activity, whereas fragments containing C2, which is highly homologous to C1, have low deposition activity. Digestion of ECM with hyaluronidase from bovine testis releases Del1 from the ECM, suggesting that glycosaminoglycans are involved in the deposition of Del1. In vivo gene transfer experiments have shown that fusion with the deposition domain of Del1 dramatically alters the distribution of exogenous proteins in mice. Thus, the extent of Del1 deposition may modify the organization of the ECM.

Background Myocardial crypts are narrow, blood-filled invaginations within the left ventricle (LV) wall and detected by cardiovascular magnetic resonance (CMR). Recent studies show that a higher prevalence of crypts in patients with hypertrophic cardiomyopathy (HCM) and genotype positive but phenotype negative relatives. Other studies show that myocardial crypts are relatively common in the normal population and incidental variants of local myocardial structures. However, these studies were performed in the western countries and the prevalence and kinds of HCM are different between Japanese and Western people. We aimed to investigate the prevalence and characteristics of myocardial crypts in Japanese people by using CMR. Methods We examined retrospectively 266 consecutive patients (mean age 63.0±15.4 years, 65.8% male) referred for CMR. Crypts were defined as >50% invagination into normal myocardium. We performed 1.5T cardiac MRI including conventional cine imaging and late gadolinium enhancement (LGE) imaging. The location and the number of crypts were evaluated by using a 17-segment model. The prevalence of crypts was compared between patients groups. We also investigated the location of LGE, family history and the first recognition of abnormal ECG in the patients with crypts. Results Crypts were identified in 12 patients (4.5%). Among them, ten patients were with HCM (83%) and 1 patient with congenital heart disease and 1 patient with arrhythmia but with normal structural heart. The prevalence of myocardial crypt is significantly higher in patients with HCM (10 of 82: 12.2%) than in patients without HCM (2 of 184: 1.1%) (P=0.0002). In 10 patients with HCM and crypt, 3 patients had apical hypertrophy. There was no significant difference in prevalence of crypts between HCM patients with apical hypertrophy and those without apical hypertrophy (3 of 23:13.0%, 7 of 59: 11.8%, respectively). Eight patients had single crypt and 4 patients had multiple crypts. All patients had at least one crypt at LV basal level and most popular location was LV basal inferior wall (10 patients). LGE was found in 6 patients and all were with HCM. Two patients had LGE in the same segment with crypt. There were 5 patients with HCM with family histories of sudden death or LV hypertrophy or dilated cardiomyopathy, but no patient without HCM had family history. Abnormal ECG findings were detected under age of 20 in four patients with HCM but in no patients without HCM. Conclusions Myocardial crypts were more frequently seen in the patients with HCM and also seen in the patients with other cardiac diseases in Japan. Although genetic tests were not performed in these patients, genetic factors were suggested in the patients with myocardial crypts and HCM. Funding N/A.

Objective Heart rate variability (HRV) has been reported to be an independent predictor of all-cause and sudden cardiac death in patients with heart failure. In the aging heart, however, both autonomic and cardiac functions appear to be altered. We assessed the relationship between aging and responsiveness of HRV and ventricular remodeling to beta-adrenergic blockade therapy in patients with heart failure and reduced ejection fraction (HFREF). Methods Twenty-eight clinically stable patients with chronic heart failure, sinus rhythm, and left ventricular ejection fraction Results HR decreased in all groups after carvedilol treatment, but was still highest in the youngest group despite the same treatment doses. Time and frequency domain variables improved. The response of time domain variables (the standard deviation of all normal sinus to normal sinus [NN] intervals and the standard deviation of the averages of NN intervals in all 5-minute or 30-minute segments) to carvedilol therapy significantly decreased with increasing age. Ventricular reverse remodeling induced by carvedilol therapy significantly decreased with increasing age. Increases in time domain variables and a low-frequency domain moderately correlated with left ventricular reverse remodeling. Conclusion Beta-adrenergic blockade therapy improved HRV variables and ventricular remodeling in HFREF patients; however, the response tended to be milder in the elderly. HRV improvement was associated with ventricular reverse remodeling.

In the present study, we established transgenic mice overexpressing Del1, a ligand of integrins, to examine the effect of overexpression of Del1 on vascular morphogenesis. In the wild-type mouse, mesenteric vessels are shaped like rakes consisting of a long stalk and short branches at the periphery. In contrast, those in transgenic mice showed typical dendritic architecture consisting of a few large primary branches with smaller spreading branches. The phenotype of mice overexpressing Del1 suggests the existence of a tissue-specific mechanism for branching morphogenesis in the mesentery. © 2005 Wiley-Liss, Inc.

Endothelin-1 (ET-1) is considered to be involved in various cardiovascular and renal disorders. The objective of this study was to investigate whether a vasodilator and antiplatelet agent, 1,4-bis[3-(3,4,5-trimethoxybenzoyloxy) propyl]perhydro-1,4-diazepine dihydrochloride monohydrate (dilazep, DZ), has an ET-1-inhibiting effect in vitro. Bovine aortic endothelial cells (BAEC) and human umbilical vein endothelial cells (HUVEC) pretreated with fetal calf serum were treated with DZ and preproET-1 (PpET-1) transcription was evaluated by Northern blot analysis. ET-1 peptide release in culture medium was evaluated by radioimmunoassay. The effect of DZ on the ET-1 promoter/enhancer apparatus was evaluated in transfection experiments using -5 kb ET-1 promoter/enhancer constructs. Modest inhibition of PpET-1 gene transcription was detected after 30 min of DZ treatment (0.56+/-0.19 vs. 1 , p

Post-transcriptional regulation plays a pivotal role in gene expression. In this study, the intracellular distribution of the murine cytoplasmic poly(C)-binding protein (alphaCP2) gene transcript was investigated. The nucleocytoplasmic mRNA distribution of alphaCP2 was shown to change throughout the course of mouse development. Furthermore, in situ hybridization of the embryo revealed that the alphaCP2 transcript was widely distributed in the cytoplasm of endothelial cells and cardiac myocytes, but accumulated in the nuclei of other cells. In the adult, alphaCP2 was ubiquitously expressed and alphaCP2 mRNA was found to accumulate in the nucleus. In vitro experiments showed that the nucleocytoplasmic mRNA distribution of alphaCP2 mRNA was distinct from that of the GAPDH gene used as an internal control. These results suggest that the intracellular distribution of alphaCP2 mRNA is developmentally regulated in a gene and/or cell specific manner.

Background: Takayasu arteritis is associated with a low incidence of coronary artery involvement, such as stenosis, obstruction, aneurysm, and coronary steal syndrome, but coronary ischemia can be fatal. Methods: Between 1972 and April 2001, 81 of 130 patients given a diagnosis of Takayasu arteritis underwent selective coronary angiography, and among them, 31 patients (4 male and 27 female patients; mean age, 41.1 ± 13.2 years) had abnormal coronary angiographic findings and were recruited for this study. Results: Abnormal coronary findings consisted of 24 coronary artery stenoses of greater than 75%, 3 coronary artery-bronchial artery anastomoses, 3 aneurysmal coronary ectasias, and 1 combined coronary ectasia and anastomosis. Among 24 patients with coronary stenosis, the ostium was most frequently involved (87.5%). Twenty-three of 24 patients with coronary artery stenoses were treated surgically. The mean follow-up duration was 9.65 ± 6.9 years, with a 100% follow-up rate. Four fistulas and 4 aneurysms in 7 patients were not treated surgically. Coronary steal phenomenon was always associated with occluded pulmonary arteries and pulmonary hypertension. Aneurysmal coronary ectasia was related to severe aortic hypertension with or without aortic regurgitation and atypical coarctation. There were 2 (8.7%) in-hospital deaths and 3 (13%) late deaths. The actuarial survival rate, including in-hospital deaths, was 86.5% ± 7.3% at 5 years and 81.4% ± 8.4% at 10 years. Conclusion: The incidence of coronary abnormalities is relatively low in patients with Takayasu arteritis; however, surgical treatment is recommended for patients with coronary ostial stenoses because coronary ischemia can be one of the major causes of death. J Thorac Cardiovasc Surg 2003;125:570-7

Objective: Cystic medial degeneration (CMD) is a histologic abnormality that is common in aortic diseases such as aortic dilation, aneurysm, or dissection. Although little is known about the mechanism underlying CMD, we have previously demonstrated that angiotensin II signaling via angiotensin II type 2 receptor (AT2R) plays a central role in apoptosis of vascular smooth muscle cells (VSMCs) occurring in CMD associated with Marfan syndrome. The aim of this study is to elucidate the role of angiotensin II signaling in THE pathogenesis of aortic diseases associated with CMD. Method: We investigated the effects of angiotensin-converting enzyme inhibitor (ACEI), temocapril (n = 15), angiotensin II receptor type-1 (AT1R) blocker, CS-866 (n = 15), and vehicle control (n = 17) on 0.25% β-aminopropionitrile monofumarate (BAPN)-induced aortic dissection and histopathologic findings in a rat model. Results: Temocapril significantly prevented aortic dissection (P < .05), CMD (P < .01), and VSMC apoptosis (P < .01) compared with vehicle control in BAPN-fed rats. However, CS-866 did not show any preventive effect. Reversed transcriptase-polymerase chain reaction demonstrated that expression of both AT1R and AT2R was detected in control rat aortas, and that AT2R expression was significantly upregulated in the aortas of BAPN-fed rats (P < .01). Blood pressure was significantly and equally lowered in both temocapril and CS-866 groups compared with control. Conclusions: Differential expression of angiotensin II receptors and AT2R signaling are involved in the pathogenesis of CMD and aortic dissection in BAPN-fed rats. ACEIs might be of clinical value for the prevention and treatment of aortic diseases related to CMD. (J Vasc Surg 2002;36:818-23.)

Aims HMG-CoA reductase inhibitors (statins) have been demonstrated to have in vitro vascular effects. The aim of this study was to determine whether statins actually have in vivo vascular effects independent of their cholesterol-lowering effect.

Aim: Abdominal aortic aneurysm (AAA) is a common vascular degenerative disease. AAA wall contains inflammatory cells that produce matrix metalloproteinases (MMPs) that probably contribute to elastolysis and remodeling of the aneurysm. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to reduce the expression of various molecules (including MMPs) independently of their cholesterol-lowering effect. The aims of this study are to investigate whether statins could modulate the biology of AAA wall and have a potential therapeutic value against AAAs. Methods: We performed immunohistochemical analysis, evaluated MMP-9 production in the aortic wall from patients with infrarenal AAA (n = 10) and control patients with aortoiliac occlusive disease (n = 8), and examined the effect of cerivastatin on MMP-9 production in the AAA wall with organ culture. Results: Neutrophils and macrophages were the cellular sources of MMP-9 in the AAA wall. The tissue concentrations of both total and active MMP-9 were significantly higher in tissues from AAA walls than in control aortic walls. Cerivastatin (0.001 to 0.1 μmol/L) significantly reduced the tissue levels of both total and active MMP-9 in a concentration-dependent manner (P < .001), and the production of tissue inhibitor of MMP-1 was unaffected. Cerivastatin neither reduced the number of infiltrating neutrophils and macrophages nor enhanced apoptosis of those cells, as evaluated with terminal transferase-mediated deoxyurisine triphosphate nick end labeling. Conclusion: These results suggest that cerivastatin can directly modulate the biology of the AAA wall and suppress MMP-9 production in the AAA wall by inhibiting the activation of neutrophils and macrophages, indicating that statin therapy could be useful for the prevention or treatment of AAA. (J Vasc Surg 2002;36:158-63.)

Pimobendan is an inotropic and vasodilating drug with phosphodiesterase (PDE) III-inhibiting and calcium-sensitizing effects. It may also have a bronchodilatory effect by inhibiting PDE III in airway smooth muscle. We tried a beta-blocker combined with low-dose pimobendan in 2 patients who had refractory heart failure of NYHA functional class III or IV with idiopathic dilated cardiomyopathy (DCM) and chronic obstructive pulmonary disease (COPD). Both of them had previously failed to tolerate beta-blocking drugs because of the exacerbation of bronchospasm. After pimobendan was administered at 1.25 to 2.5 mg daily, metoprolol could be successfully introduced from a low dose of 1.25 mg daily without decreasing the peak expiratory flow rate. Over the next 1 to 2 years, they have continued beta-blocker therapy. One is currently receiving 10 mg daily of bisoprolol and another is taking 15 mg daily of metoprolol, and both are in NYHA functional class II without worsening heart failure or COPD. The combination of beta-blocker with low-dose pimobendan may be helpful for patients with DCM and COPD, but further clinical investigation is required.

To determine whether adequate myocardial perfusion status after transluminal recanalization is associated with prompt improvement of QT dispersion (QTd).Transluminal recanalization of the infarct-related coronary artery in acute myocardial infarction aims to promptly restore myocardial perfusion, to maximize electrical and mechanical recovery. QTd represents the heterogeneity of ventricular repolarization, which may affect electrical stability.Forty patients who underwent primary percutaneous coronary intervention for their first anterior acute ST-elevation myocardial infarction were prospectively enrolled. Myocardial reperfusion status was assessed by myocardial blush grade (MBG) on the final angiogram after successful recanalization (Thrombolysis In Myocardial Infarction Grade 3 flow).Preprocedural QTd was similar in patients with final MBG 0-1, 2, and 3 (76 ± 24, 67 ± 13, and 69 ± 13 milliseconds, respectively; P = 0.661). After recanalization, QTd decreased in patients with MBG 3 (39 ± 16 milliseconds, P 0.001) but not in patients with MBG 0-1 (74 ± 20 milliseconds) or MBG 2 (82 ± 16 milliseconds). Multivariate analysis showed that postprocedural MBG was an independent predictor of QTd after recanalization (standardized regression coefficient = -0.628, P 0.001).Adequate tissue perfusion may be crucial for electrical stability of the myocardium after reperfusion.

Retinoids have been shown to inhibit cell growth, which can result in an anti-atherosclerotic action in the vasculature. Endothelin-1 (ET-1), a potent vasoconstrictor peptide produced in endothelial cells, plays an important role in inducing proliferation of vascular smooth muscle cells. In this study, we investigated the effect of retinoids on the mRNA expression and transcriptional activity of the ET-1 gene in endothelial cells. All-trans retinoic acid (ATRA) suppressed ET-1 mRNA expression in cultured endothelial cells. Synthetic retinoids, Ch55 and Am580 (retinoic acid receptor (RAR) agonists) markedly enhanced this effect, and an RAR antagonist, LE540, blocked this inhibitory effect on ET-1 gene expression. ATRA did not change ET-1 mRNA half-life. Transfection experiments using 5 kb of the ET-1 promoter-reporter gene construct which contains 5 kb of the preproET-1 promoter revealed that ATRA and Ch55 suppressed ET-1 promoter activity, resulting in down-regulation of ET-1 gene transcription. Taken together, retinoids may be another modulator of endothelial cell function through regulation of vasoactive substances at the transcription level.

Background —Little is known regarding intravascular ultrasound (IVUS) criteria to determine the functional severity of coronary stenosis. Recently, fractional flow reserve (FFR) has emerged as a lesion-specific index of the functional severity of a coronary stenosis that is independent of systemic hemodynamic variability. The present study was undertaken to determine the IVUS parameters for the physiological severity of coronary stenosis. Methods and Results —Fifty-one lesions in 42 patients were evaluated by means of quantitative coronary angiogram, IVUS, and intracoronary pressure measurements. The FFR was calculated as the ratio of the distal coronary pressure divided by the proximal coronary pressure under hyperemia. We considered a value of the FFR r 2 =0.62, P r 2 =0.60, P 2 (sensitivity, 83.0%; specificity, 92.3%) and area stenosis >0.6 (sensitivity, 92.0%; specificity, 88.5%). The combination of both criteria (MLA 2 and area stenosis Conclusions —Anatomic parameters obtained by IVUS showed a significant correlation to the FFR values. The present study demonstrated that the combination of the MLA and area stenosis measured by IVUS can be an anatomic predictor for the physiological impact of coronary epicardial stenosis.

We have taken advantage of an enhancer trap event in a line of transgenic mice to identify a unique developmentally regulated endothelial cell locus (Del1). The protein encoded in this locus contains three EGF-like repeats homologous to those in Notch and related proteins, including an EGF-like repeat that contains an RGD motif, and two discoidin I-like domains. Del1 is shown to be a matrix protein and to promote adhesion of endothelial cells through interaction with the αvβ3 integrin receptor. Embryonic endothelial-like yolk sac cells expressing recombinant Del1 protein, or grown on an extracellular matrix containing Del1 protein, are inhibited from forming vascular-like structures. Expression of Del1 protein in the chick chorioallantoic membrane leads to loss of vascular integrity and promotes vessel remodeling. Del1 is thus a new ligand for the αvβ3 integrin receptor and may function to regulate vascular morphogenesis or remodeling in embryonic development.

The cyclic AMP (cAMP)-dependent chloride channel in the heart has been identified in various species as the cystic fibrosis transmembrane conductance regulator (CFTR). Although functional expression of the channel in the human atrium has been reported, we could not induce any cAMP-dependent chloride conductance in the atrial cells even with maximal cAMP stimulation, whereas the conductance could be induced in rabbit ventricular cells. To clarify the discrepancy between the results, we examined the level of CFTR mRNA expression in both conductance-positive (human colonic epithelium and rabbit ventricle) and -negative (human atrium) tissues. Total RNA samples prepared from these tissues were subjected to the reverse transcription-polymerase chain reaction (RT-PCR). While CFTR transcripts were amplified from the conductance-positive samples, no amplified products could be detected from the conductance-negative sample. A nested PCR performed on the RT-PCR products of the conductance-negative sample resulted in successful amplification of the transcripts, indicating that the level of the CFTR mRNA expression in human atrium is extremely low compared with that in colonic epithelium and rabbit ventricle. The same molecular results were observed in human ventricular tissues. A nucleotide sequencing of the amplified transcripts showed that exon 5 of the CFTR gene was not alternatively spliced in human atrium and ventricle, and both the exon 5 spliced and unspliced isoforms were expressed in rabbit ventricle, unlike the findings of previous reports. Our data suggest that the amount of CFTR expressed in human myocardium might be physiologically insufficient to activate detectable cAMP-dependent chloride conductance.

methods: A total of 1055 adults (mean age 63±13, 58.8% men) without diabetes mellitus, systolic dysfunction or other heart disease underwent a thorough physical examination including tissue Doppler echocardiography. We designated peak early mitral annular velocity (e’) of less than 5.0 to indicate abnormal LV myocardial relaxation (LVMR). We performed single and multiple logistic regression analyses of e’ and cardiovascular risk factors, including MetS factors and indicators of major organ dysfunction and evaluated results with regard to three age groups: young (≤ 49 yrs), middle-aged (50-69 yrs) and elderly (≥ 70 yrs) for both men and women.

The role of endothelin (ET) in acute myocardial infarction and proarrhythmic potential was investigated in a rabbit model. One group of rabbits underwent 30 min of circumflex occlusion and 3 h of reperfusion with measurements of myocardial blood flow and myocardial levels of ET-1 messenger RNA (mRNA). In a second group, the systemic and coronary effects of exogenous ET were studied in animals pretreated with either saline, FR139317, an ETA-receptor antagonist, or PD145065, an ET A - and ET B -receptor antagonist. In a third study, animals undergoing 30 min of circumflex occlusion followed by 48 h of reperfusion were treated with exogenous ET-1, FR139317, PD145065, or saline. Arrhythmias were recorded and infarct size measured at 48 h. These studies revealed that ischemia and reperfusion was followed by a progressive microcirculatory failure (no-reflow phenomenon) in rabbits. This was associated with a 2.6-fold elevation in levels of myocardial ET-1 mRNA in the ischemic zone in comparison to the nonischemic zone (p = 0.04). Exogenous ET-1 caused elevation in coronary and systemic vascular resistance that was significantly blocked by antagonism of the ET A receptor. In rabbits subjected to myocardial ischemia and reperfusion, ET- I infusion led to a higher incidence of ventricular arrhythmias, whereas ET-receptor antagonism with PD145065 significantly reduced ventricular arrhythmias. Exogenous ET-1 and FR139317 failed to alter infarct size (AN) of the area at risk (AR) compared with control [AN/AR(%) was 46 ± 8, 55 ± 9, and 47 ± 7, respectively]. However, PD145065 significantly decreased AN/AR (22 ± 7; p ≤ 0.02). The increased production of ET-1, resulting from increased levels of mRNA after reperfusion, may contribute to the no-reflow phenomenon. Although the vasoconstrictor effects of ET- I can be blocked by ET A -receptor antagonism alone, only blockade of both the ET A and ET B receptors significantly reduced infarct size. These data suggest that production of ET increases in the heart during ischemia and is deleterious to the reperfused myocardium.

Objectives.We investigated the role of endogenous endothelin-1 in the development of cardiac hypertrophy in vivo under pressure overload conditions.Background.Endothelin-1, a potent vasoconstrictor peptide, has recently been shown to act as a growth factor of myocardial cells in culture.Methods.We examined the effect of an endothelin-A receptor antagonist (FR139317) on the development of right ventricular hypertrophy in rats with monocrotaline-induced pulmonary hypertension. Three groups of rats were studied: those given monocrotaline alone or monocrotaline plus FR139317 and those given vehicle alone (control group).Results.The ratio of right ventricular systolic pressure to aortic systolic pressure was similarly elevated in rats treated with monocrotaline and monocrotaline plus FR139317. The right ventricular/left ventricular weight ratio was increased in monocrotaline-treated rats but lower in rats treated with monocrotaline plus FR139317 than in those treated with monocrotaline alone (p < 0.01). As a biochemical marker of hypertrophy, the isoform ratio of beta-myosin heavy chain protein was determined for the right ventricular tissue samples. This ratio was increased in all monocrotaline-treated rats but was lower (p < 0.01) in rats given monocrotaline plus FR139317 than in those given monocrotaline alone. The isoform ratio of beta-myosin heavy chain messenger ribonucleic acid quantitated by S1 nuclease mapping also was lower (p < 0.025) in rats receiving monocrotaline plus FR139317 than in those receiving monocrotaline alone.Conclusions.These data suggest that blocking the action of endothelin-1 with a receptor antagonist ameliorates cardiac hypertrophy in this model system, and that this action is not mediated by ameliorating hemodynamic changes.