Background: The presence of coronary vulnerable plaque has been shown to increase the risk of myocardial damage after percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI) patients. It is possible that coronary plaque vulnerability may be assessed by evaluating plaque characteristics in other vessels such as the carotid arteries. Contrast-enhanced ultrasound (CEUS) of carotid plaque has been shown to detect the plaque neovascularization of carotid plaques, which is a feature of vulnerable plaque. Thus, in this study we examined whether CEUS of the carotid artery may provide information for myocardial damage risks after PCI in STEMI patients. Methods and Results: CEUS of the carotid plaques using perfluorobutane microbubbles as an ultrasound contrast agent were performed in consecutive 95 STEMI patients treated with emergent PCI. Intraplaque neovascularization was identified on the basis of microbubbles within the carotid plaque and graded as: G0, not visible; G1, moderate; or G2, extensive microbubbles. Obtained coronary flow and myocardial damage after PCI were estimated by corrected TIMI frame count (cTFC), Myocardial Blush Grade (MBG), peak CK-MB and Troponin T. The presence of G2 in the carotid arteries was associated with higher levels of cTFC (G0, 34±19 frames; G1, 41±21 frames; 43±24 frames,ρ=0.005) , lower levels of MBG (G0, 2.3±0.7; G1, 1.7±0.9; G2, 1.5±0.9,ρ=0.013), and higher levels of carotid IMT, fast blood glucose, hemoglobin A1c, hsCRP, and troponin T (ρ=0.049, 0.042, 0.046, 0.048, 0.01, and 0.02). Conclusion: The presence of carotid plaque neovascularization was related with myocardial damage after PCI in STEMI patients. Measurement of CEUS of Carotid Plaque is useful for risk stratification of STEMI patients underwent emergent PCI.
Periostin, which is an extracellular matrix (ECM) molecule of the fasciclin family, acts in cell adhesion, migration, and growth in vitro ( 1 -6 ).In the heart, periostin is expressed at very early stages of embryogenesis; however, it is not detected in the normal adult myocardium, except in the valves ( 7, 8 ) and in the case of various heart diseases ( 9 -12 ).The early cardiac healing process after acute myocardial infarction (AMI) can be divided into two successive phases: the infl ammatory phase and the scar formation phase.In the infl ammatory phase, monocytes and lymphocytes infi ltrate into the necrotic myocardium, whereas in the scar formation phase, activated interstitial or circulating fi broblasts increase their motility and migrate into the lesion.The activation of TGF  is important for regulation of this latter process.Myofi broblasts expressing ␣ smooth muscle actin ( ␣ SMA) induced by TGF  are specialized fi broblasts that share characteristics with smooth muscle cells (SMCs).They play an important role in wound healing by synthesizing ECM and exerting strong contraction forces to minimize wound areas ( 13 -16 ).Regarding the infl ammatory phase, recent knockout mouse studies indicated a positive association of infl ammatory factors with cardiac rupture or dilation ( 17 -23 ).However, in the scar formation phase, molecular analysis has been scant, except in respect to TGF  .To answer two important questions for both cardiologists and basic scientists who are interested in pathological myocardial healing, i.e., " what regulates formation of
Background: The ATP-binding cassette transporter BCRP1/ABCG2 has been shown to be expressed in various normal organs including the heart, and has been suggested to regulate several tissue defense mechanisms via modulation of survival and function of BCRP1/ABCG2-expressing cells besides active efflux of toxins. However, its physiological significance in cardiac repair after myocardial infarction (MI) remains unknown. Methods and Results: Immunohistochemistry showed that BCRP1/ABCG2 was mainly expressed in endothelial cells of microvessels in the heart. MI was induced in 8- to 12-week-old wild-type (WT) and Bcrp1/Abcg2 knock-out (KO) mice by ligating the left anterior descending artery. In the absence of MI, cardiac function and morphology did not differ between WT and KO mice. At 28 days after MI, survival rate was significantly lower in KO mice than in WT mice mainly due to cardiac rupture (28.3%, n=60, versus 74.5%, n=51, p Conclusions: BCRP1/ABCG2 plays a pivotal role in cardiac repair after MI via modulation of microvascular endothelial cell survival and function. BCRP1/ABCG2 might be of interest for a therapeutic target to improve post-MI outcomes.
BackgroundUltrasound assessment of the carotid artery provides prognostic information on coronary events. This study examined whether ultrasound assessments of plaque echolucency of the carotid artery are useful for identifying patients with coronary artery disease (CAD) who are at high risk but could benefit from lipid-lowering therapy for secondary prevention.MethodsUltrasound assessment of carotid plaque echolucency with integrated backscatter (IBS) analysis was performed in 393 chronic CAD patients with low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dL on statin therapy. All patients were prospectively followed up for a maximum of 96 months or until the occurrence of one of the following coronary events: cardiac death, nonfatal myocardial infarction, or unstable angina pectoris requiring unplanned revascularization.ResultsDuring the follow-up period, 45 coronary events occurred. Patients were stratified by IBS (≤-16.3 or >-16.3 dB, median value) and LDL-C level (<70 or 70–99 mg/dL). Multivariate Cox proportional hazards analysis showed that patients with lower IBS and LDL-C 70–99 mg/dL had significantly higher probabilities of coronary events compared with those with higher IBS and LDL-C <70 mg/dL, after adjustment for a baseline model of risk factors (hazard ratio 5.15; 95% confidence interval 1.21–22.0, p = 0.03). In contrast, patients with lower IBS and LDL-C <70 mg/dL had an improved prognosis comparable with those with higher IBS. Addition of LDL-C levels to the baseline model of risk factors improved net reclassification improvement (NRI) and integrated discrimination improvement (IDI) in patients with lower IBS (NRI, 0.44, p = 0.04; and IDI, 0.035, p < 0.01), but not in those with higher IBS.ConclusionsEvaluation of echolucency of the carotid artery was useful for selecting CAD patients at high risk of secondary coronary events but who could benefit from lipid-lowering therapy.
5529 Background: LACvCa has a poor prognosis. CCRT is the standard treatment for LACvCa, and the 5-year survival rate is estimated at around 60%. Nivolumab (Nivo), an anti-PD1 monoclonal antibody, showed clinical activity in recurrent or persistent CvCa pts. Nivo may enhance antitumor immune responses induced by CCRT. The safety and feasibility of Nivo plus CCRT for LACvCa pts has not yet been reported. We report data from a phase I trial evaluating safety and feasibility of pre- and co-administration of Nivo with CCRT in pts with LACvCa (GOTIC-018; JMA-IIA00425). Methods: The treatment plan in cohort A is co-administration of Nivo (240mg/body once every 2 weeks) with CCRT followed by maintenance therapy with Nivo. The treatment plan in cohort B is pre- (two doses of Nivo before CCRT) and then co-administration of Nivo with CCRT followed by Nivo maintenance. The CCRT regimen includes 4 or more cycles of cisplatin (40 mg/m 2 weekly) and external beam radiotherapy (EBRT) followed by brachytherapy. The Nivo maintenance therapy was scheduled for 52 weeks after completion of CCRT. The primary objective is the rate of Grade≧3 adverse events (AEs) during the acute phase, which is defined as 90 days from the start date of EBRT. Secondary objectives include the incidence of dose limiting toxicity (DLT) and progression-free survival. Results: A total of 30 patients, 15 patients in each cohort, was enrolled in this study. This report is a safety evaluation in the acute phase of the study. There were 1 stage IVA, 11 stage IIIB, 16 stage II and 2 stage IB tumors based on FIGO 2009. 28 squamous cell and 2 adeno/adenosquamous carcinomas were included. No DLT was observed in the first 6 DLT-evaluable pts in each cohort. All 30 patients completed planned EBRT and brachytherapy. 2 and 0 patients required a break from EBRT in cohort A and B, respectively. The median cycles of cisplatin administration was 5 and 6 in cohort A and B, respectively. 2 and 0 patient required cisplatin dose reduction in cohort A and B, respectively. 1 patient required cisplatin discontinuation in each cohort. The median cycles of Nivo administration were 6 and 9 in cohort A and B, respectively. 1 patient required Nivo discontinuation due to AEs in each cohort. All patients experienced Grade≧3 AEs. Most common Grade≧3 AEs were neutropenia (60.0 and 26.7% in cohort A and B, respectively), anemia (13.3 and 16.7%) and diarrhea (13.3 and 26.7%). In cohort B, no patients required delay in starting CCRT due to the AEs related to pre-administration of Nivo, and no patients had disease progression before starting CCRT. Conclusions: No DLT was reported during the acute phase in both cohort A and B, and no new safety signals were observed. Addition of pre-and co- administration of Nivo appears safe and feasible in patients with LACvCa treated with CCRT. Clinical trial information: JMA-IIA00425.
Glucose-regulated protein, 78-kilodalton (GRP78) is a molecular chaperone that exists in the endoplasmic reticulum and is involved in the assembly, transportation, and folding of proteins. Previously, GRP78 was reported to associate with gonadotropin receptors. However, little is known about how GRP78 is involved in the regulation of luteinizing hormone receptor (LHR). Thus, in this study, we investigated the significance of GRP78 for the induction of LHR in rat luteinizing granulosa cells. Western blot analysis of rat LHR expressed in HEK293 cells revealed that the protein levels of LHR were increased, depending on the increment of GRP78 protein. In both in vivo and in vitro experiments, the GRP78 mRNA level peaked while LHR mRNA was down-regulated by human chorionic gonadotropin (hCG). To examine the time-dependent localization of GRP78 in vivo, immunohistochemistry was performed. GRP78 was expressed mainly in granulosa cells, and the GRP78 protein peaked 18 h after the ovulatory dose of hCG injection in equine chorionic gonadotropin-primed immature rats. To ascertain the role of GRP78 in LHR after down-regulation, small interfering GRP78 was transfected to cultured rat granulosa cells, demonstrating that knockdown of the GRP78 protein level impaired the recovery of cell surface LHR from down-regulation that negatively affected progesterone synthesis. Moreover, luciferase assays showed that CRE mediated the hCG-induced promoter activity of GRP78 in rat luteinizing granulosa cells. These results reveal a novel mechanism of LHR by GRP78 in the early stage of corpus lustrum formation, which may be an important factor in the recovery of LHR after the down-regulation.
Background: Reduced insulin secretion is linked to diabetes and cardiovascular disease (CVD), but its role in non-diabetic CVD patients is unclear. The homeostasis model assessment of β-cell function (HOMA-β) measures pancreatic β-cell function. This study investigated the association between HOMA-β and adverse cardiovascular events in non-diabetic CVD patients.
The 78-kilodalton glucose-regulated protein (GRP78) is a molecular chaperone that assists in protein assembly, folding, and translocation. Recently, our laboratory reported that GRP78 regulates the expression of luteinizing hormone-human chorionic gonadotropin receptor (LHR) in the early stage of corpus luteum formation. In this study, we investigated whether microRNAs (miRNAs), which post-transcriptionally regulate mRNA, are involved in the regulation mechanism of GRP78 in the ovary. A miRNA microarray was performed to analyze the overall miRNA expression profile, and the results indicated that 44 miRNAs were expressed highly after ovulation was induced. The results from a bio-informative database analysis and in vitro granulosa cell culture studies led us to focus on rno-miR-376a for further analysis. In both in vivo and in vitro studies, rno-miR-376a levels increased 12 h after human chorionic gonadotropin (hCG) administration. To elucidate whether rno-miR-376a induced mRNA destabilization or translational repression of GRP78, rno-miR-376a was transfected into cultured granulosa cells, resulting in decreased GPR78 protein levels without an alteration in GRP78 mRNA levels. To confirm that rno-miR-376a binds to GRP78 mRNA, we cloned the 3′-end of GRP78 mRNA (nucleotides 2439–2459) into a reporter vector that contained a Renilla luciferase coding region upstream of the cloning site. The luciferase assays revealed that rno-miR-376a bound to the 3′-end of GRP78 mRNA. From these data, we conclude that rno-miR-376a potentially negatively regulates GRP78 protein expression through translational repression at an early stage transition from the follicular phase to luteinization.
