Aims: There are limited data on the management and outcomes of chronic liver disease (CLD) patients presenting with acute myocardial infarction (AMI), particularly according to the subtype of CLD. Methods: Using the Nationwide Inpatient Sample (2004-2015), we examined outcomes of AMI patients stratified by severity and sub-types of CLD. Multivariable logistic regression was performed to assess the adjusted odds ratios (aOR) of receipt of invasive management and adverse outcomes in CLD groups compared with no-CLD. Results: Of 7 024 723 AMI admissions, 54 283 (0.8%) had a CLD diagnosis. CLD patients were less likely to undergo coronary angiography (CA) and percutaneous coronary intervention (PCI) (aOR 0.62, 95%CI 0.60-0.63 and 0.59, 95%CI 0.58-0.60, respectively), and had increased odds of adverse outcomes including major adverse cardiovascular and cerebrovascular events (1.19, 95%CI 1.15-1.23), mortality (1.30, 95%CI 1.25-1.34) and major bleeding (1.74, 95%CI 1.67-1.81). In comparison to the non-severe CLD sub-groups, patients with all forms of severe CLD had the lower utilization of CA and PCI (P <.05). Among severe CLD patients, those with alcohol-related liver disease (ALD) had the lowest utilization of CA and PCI; patients with ALD and other CLD (OCLD) had more adverse outcomes than the viral hepatitis sub-group (P <.05). Conclusions: CLD patients presenting with AMI are less likely to receive invasive management and are associated with worse clinical outcomes. Further differences are observed depending on the type as well as severity of CLD, with the worst management and clinical outcomes observed in those with severe ALD and OCLD.

Background: Patients with pre-existing vascular disease are known to have worse outcomes after acute myocardial infarction (AMI). However, there is limited data for outcomes stratified by type and number of vascular territories involved. Methods: Using the Nationwide Inpatient Sample (2015–2017), we examined outcomes of AMI in patients with pre-existent vascular disease stratified by number as well as types of diseased beds including all five major vascular sites: cardiac, cerebrovascular, renal, aortic and peripheral vascular disease (PVD). Multivariable logistic regression was used to determine the adjusted odds ratios (aOR) of adverse outcomes and invasive procedure utilization. Results: Out of 2,184,614 AMI admissions, 49.7% had pre-existent vascular disease. The odds of major adverse cardiovascular and cerebrovascular events (MACCE), mortality, ischemic stroke and major bleeding incrementally increased and was highest in those with ≥3 vascular sites involved (aOR for MACCE 1.16, CI 1.13–1.19; mortality 1.3, CI 1.26–1.34; stroke 1.15, CI 1.1–1.2; major bleeding 1.21, CI 1.16–1.25). Amongst those with a single pre-existent diseased vascular bed, the adjusted odds of MACCE appeared to be higher in those with PVD (1.28, CI 1.26–1.31), aortic disease (1.24, CI 1.19–1.29), and cerebrovascular disease (1.22, CI 1.2–1.25). Patients with pre-existent vascular disease had a lower overall likelihood of undergoing invasive revascularization procedures. Conclusions: Approximately half of the population presenting with AMI have pre-existent vascular disease. There is an incremental increase in adverse outcomes with increasing number of diseased vascular beds, with further differences in outcomes and utilization of invasive procedures based on sub-types of sites involved.

No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / Recent clinical outcome studies demonstrate that Sodium glucose cotransporter 2 inhibitors (SGLT2i) significantly reduce major adverse cardiovascular events and heart failure outcomes in subjects with type 2 diabetes mellitus. At present, several hypotheses have been proposed to explain the observed cardiovascular benefit of SGLT2i, however, the mechanisms responsible remain to be elucidated. This investigation tested the hypothesis that SGLT2i improves cardiac function and efficiency during acute, regional ischemia/reperfusion injury via preferential shifts in myocardial substrate selection and/or inhibition of cardiac sodium/hydrogen exchanger-1 (NHE-1). Our initial investigation evaluated the effects of 24 hour pretreatment of the SGLT2i canagliflozin on cardiac contractile function, substrate utilization, and efficiency before and during regional myocardial ischemia/reperfusion injury in healthy swine. At the onset of ischemia, canagliflozin increased left ventricular end diastolic and systolic volumes which returned to baseline with reperfusion. This increased end diastolic volume was directly associated with increased stroke volume and stroke work relative to controls during ischemia. Canagliflozin also increased cardiac work efficiency during ischemia relative to control swine. No differences in myocardial substrate uptake of glucose, lactate, fatty acids or ketones were detected between groups. In separate experiments using a longer 60 min coronary occlusion, canagliflozin significantly diminished myocardial infarct size. Subsequent studies investigated the effect of an acute administration (15-30 min pre-treatment) of canagliflozin and the NHE-1i cariporide on cardiac contractile function efficiency in response to myocardial ischemia/reperfusion injury. Similar to our initial studies, canagliflozin increased diastolic filling, stroke work and improved cardiac work efficiency relative to untreated control hearts during the ischemic period. In contrast, cariporide did not alter ventricular filling volume, cardiac output or work efficiency at any time point. Additional examination of AP-1 cells transfected with wild-type NHE-1 showed dose-dependent inhibition of NHE-1 activity by cariporide, while canagliflozin had minimal effect on overall activity. This investigation demonstrates that SGLT2i improves cardiac function and efficiency during acute, regional ischemia in healthy swine. However, the present data fail to support the hypothesis that these SGLT2i-mediated improvements involve either preferential alterations in myocardial substrate utilization or the inhibition of NHE-1 activity.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18162号 / 医博第3882号 / 新制||医||1003(附属図書館) / 31020 / 京都大学大学院医学研究科医学専攻 / (主査)教授 福原 俊一, 教授 佐藤 俊哉, 教授 坂田 隆造 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21677号 / 医博第4483号 / 新制||医||1036(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中山 健夫, 教授 木村 剛, 教授 湊谷 謙司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

No description available.

Myocardial infarction (MI) frequently occurs in patients with diabetes resulting in higher mortality and morbidity than non-diabetic patients. We and others have shown that bone marrow-derived endothelial progenitor cells (BM-EPCs) promote cardiac neovascularization and attenuate ischemic injury in animal models. Lately, emerging evidence supports that exosomes (Exo), a family of extracellular vesicles, mediate stem cell therapy by carrying cell-specific biological cargo and by inducing signaling via transferring of bioactive molecules to target cells. Despite promising results of stem cells/Exo in preclinical studies, autologous cell-based therapies yielded modest clinical results, suggesting cellular/Exo reparative function may be compromised by the presence of comorbid diseases including complications associated with diabetes. Recent studies suggest that epigenetic mechanisms, such as histone and DNA modifications for gene silencing, promote diabetes-induced vascular complication. Therefore, we hypothesized that diabetic EPCs produce exosomes of altered and dysfunctional content that compromise their reparative function in ischemic heart disease via epigenetic alterations. We collected EPC-Exo from non-diabetic (db/+) and diabetic (db/db) mice and examined their reparative effect in vitro and on permanent left anterior descending (LAD) coronary artery ligation and ischemia/reperfusion (I/R) myocardial ischemic injuries in vivo. Our data demonstrated that compared to non-diabetic EPC-Exo, diabetic EPC-Exo promoted neonatal rat cardiomyocyte cell apoptosis under hypoxic stress and repressed endothelial tube formation and cell survival. In vivo studies revealed that non-diabetic EPC-Exo treatments improved cardiac function and remodeling while diabetic EPC-Exo significantly depressed cardiac function, reduced capillary density, increased fibrosis in the permanent LAD ligation MI injury. Moreover, in the I/R MI model, we found that non-diabetic EPC-Exo mediated cardio-protection was lost compared with diabetic-EPC-Exo, and diabetic-EPC-Exo increased immune cell infiltration, infarcted area, and plasma cardiac troponin-I. Mechanistically, histone 3 lysine 9 acetylation (H3K9Ac), a gene activating histone modification, expression was decreased in mouse cardiac endothelial cells (MCECs) treated with db/db EPC-Exo compared with db/+ EPC-Exo, suggesting diabetic EPC-Exo inhibits endothelial cell gene expression. The H3K9Ac chromatin immunoprecipitation sequencing (ChIP-Seq) results further revealed that diabetic EPC-Exo reduced H3K9Ac level on angiogenic, cell survival, and proliferative genes in MCECs. Moreover, we found that a small molecular inhibitor of HDACs, valproic acid (VPA), effectively prevented diabetic EPC-Exo-medicated H3K9Ac reduction, indicating VPA may rescue the beneficial gene expression and cell function. Taken together, our results provide evidence that diabetic EPC-Exo reparative function is impaired in the ischemic heart and this may be through HDACs-mediated H3K9Ac downregulation leading to inhibition of beneficial genes in recipient cardiac endothelial cells. Reversing diabetic EPC-Exo function by treating with HDAC inhibitors may provide a new path for autologous exosome therapy for myocardial repair in diabetic patients. However, questions still remain on what the content change of stem cell-derived exosome under diabetic condition is.Emerging evidence support a key role of variety of stem /progenitor cell-secreted Exo as a pivotal paracrine entity to mitigate cardiovascular injury. Beside EPC-, cortical bone stem cell (CBSC)-, and cardiac stem/progenitor cell (CPC)- derived Exo are adequate to enhance cardiac repair and regeneration after injury. As widely acknowledged, the comorbidities such as hyperglycemia is a characteristic of diabetes and a major driving factor in CVD. The functional role of stem/progenitor cell- derived Exo and molecular signature of their secreted Exo cargo under hyperglycemic conditions remain elusive. Therefore, we hypothesize that hyperglycemic stress causes transcriptome changes in stem/progenitor cell- derived Exo that may compromise their reparative function. To identify the content change in Exo under hyperglycemia, we performed an unbiased Exo transcriptome signatures from 3 different aforementioned stem/progenitor cells by next generation exosome RNA sequencing (RNA-seq). The results indicated that the size and number of Exo were not changed from 3 stem/progenitor cells between normal and high glucose groups. Furthermore, analysis revealed differential expression of variety of RNA species in Exo and the portions of different RNA were change under hyperglycemia. Specifically, we identified 241 common-dysregulated mRNAs, 21 ncRNAs and 16 miRNAs in three stem cell-derived Exo. Based on mRNA data, Gene Ontology (GO) revealed that potential function of common mRNAs mostly involved in metabolism and transcriptional regulation. We also provided the detail information of these non-annotated ncRNAs and the potential mRNA targets by miRNA-mRNA prediction. This study not only provides potential candidates for individual stem cell types but also identifies common genes in response to hyperglycemia. These reference data are critical for future biological studies and application of stem/progenitor cell-derived Exo in ischemic heart or other diseases to prevent the adverse effects of hyperglycemia-induced stem/progenitor cell- derived Exo dysfunction. / Biomedical Sciences / Accompanied by five Microsoft Excel files: 1) Supplementary Table 1 2) Supplementary Table 2 3) Supplementary Table 3 4) Supplementary Table 4 5) Supplementary Table 5

Ischemic heart disease (IHD) accounts for the majority of heart disease-related deaths worldwide. Ubiquitin (UB), found in all eukaryotic cells, is a highly conserved low molecular weight (~8.5 kDa) protein. A well-known intracellular function of UB is to regulate protein turnover via the UB-proteasome system. UB is a normal constituent of plasma, and elevated levels of UB are observed in the serum of patients under a variety of pathological conditions. Recent studies provide evidence for cardioprotective potential of exogenous UB in the remodeling process of the heart in IHD, including effects on cardiac myocyte apoptosis, inflammatory response, and reorganization of the vasculature and extracellular matrix. This review summarizes functions of UB with an emphasis on the role of exogenous UB in myocardial remodeling in IHD.