bluuebunny/crossref_metadata_2025 huggingface dataset:
Advanced Glycation End Products (AGEs): Biochemistry, Signaling, Analytical Methods, and Epigenetic Effects
Authors: Perrone Anna , Giovino Antonio , Benny Jubina , Martinelli Federico
Published: March 2020

The advanced glycation end products (AGEs) are organic molecules formed in any living organisms with a great variety of structural and functional properties. They are considered organic markers of the glycation process. Due to their great heterogeneity, there is no specific test for their operational measurement. In this review, we have updated the most common chromatographic, colorimetric, spectroscopic, mass spectrometric, and serological methods, typically used for the determination of AGEs in biological samples. We have described their signaling and signal transduction mechanisms and cell epigenetic effects. Although mass spectrometric analysis is not widespread in the detection of AGEs at the clinical level, this technique is highly promising for the early diagnosis and therapeutics of diseases caused by AGEs. Protocols are available for high-resolution mass spectrometry of glycated proteins although they are characterized by complex machine management. Simpler procedures are available although much less precise than mass spectrometry. Among them, immunochemical tests are very common since they are able to detect AGEs in a simple and immediate way. In these years, new methodologies have been developed using an in vivo novel and noninvasive spectroscopic methods. These methods are based on the measurement of autofluorescence of AGEs. Another method consists of detecting AGEs in the human skin to detect chronic exposure, without the inconvenience of invasive methods. The aim of this review is to compare the different approaches of measuring AGEs at a clinical perspective due to their strict association with oxidative stress and inflammation.
Reliability Optimization of Structural Deformation with Improved Support Vector Regression Model
Authors: Zhu Zheng-Zheng , Feng Yun-Wen , Lu Cheng , Fei Cheng-Wei
Published: March 2020

Deformation is one important failure mode of turbine blades. The quality of a model seriously influences the reliability optimization of turbine blades in turbo machines. To improve the reliability optimization of turbine blades, this paper proposes a novel machine learning‐based reliability optimization approach, named improved support vector regression (SR) model (ISRM) method, by fusing artificial bee colony (ABC), traditional SR model, and multipopulation genetic algorithm (MPGA). In this proposed method, the ABC algorithm was applied to find the optimal parameters in the SR model to establish accurate ISRM, following the thought of the surrogate model method and the randomness of constraints. Then the reliability optimization model and procedure with the ISRM method were resolved by the MPGA. Regarding many design parameters (i.e., rotor speed, temperature, and aerodynamic pressure), design objective (i.e., blade deformation), and the randomness constraints of reliability degree and boundary conditions, we performed the reliability optimization of a turbine blade deformation. From the optimization results, we find that the turbine blade deformation is reduced by 0.09329 mm, and the ISRM learning method can improve the reliability optimization design of complex structures with the emphasis on modeling precision and optimization efficiency. The works of this paper provide a machine learning‐based reliability optimization approach for the reliability optimization of complex structures and enrich and develop mechanical reliability theory and methods.
The Achievements and Challenges of Mesenchymal Stem Cell-Based Therapy in Inflammatory Bowel Disease and Its Associated Colorectal Cancer
Authors: Ocansey Dickson Kofi Wiredu , Qiu Wei , Wang Jingyan , Yan Yongmin , Qian Hui , Zhang Xu , Xu Wenrong , Mao Fei
Published: March 2020

Approximately 18.1×106 new cases of cancer were recorded globally in 2018, out of which 9.6 million died. It is known that people who have Inflammatory Bowel Disease (IBD) turn to be prone to increased risks of developing colorectal cancer (CRC), which has global incident and mortality rates of 10.2% and 9.2%, respectively. Over the years, conventional treatments of IBD and its associated CRC have been noted to provide scarce desired results and often with severe complications. The introduction of biological agents as a better therapeutic approach has witnessed a great deal of success in both experimental and clinical models. With regard to mesenchymal stem cell (MSC) therapy, the ability of these cells to actively proliferate, undergo plastic differentiation, trigger strong immune regulation, exhibit low immunogenicity, and express abundant trophic factors has ensured their success in regenerative medicine and immune intervention therapies. Notwithstanding, MSC-based therapy is still confronted with some challenges including the likelihood of promoting tumor growth and metastasis, and possible overestimated therapeutic potentials. We review the success story of MSC-based therapy in IBD and its associated CRC as documented in experimental models and clinical trials, examining some of the challenges encountered and possible ways forward to producing an optimum MSC therapeutic imparts.
The Liver That Cured Christmas: Case Report of Orthotopic Liver Transplant in a Patient with Hemophilia B
Authors: Harris Jesse E. , Balk Jonathan L. , Mobley Constance M. , Heyne Kirk
Published: March 2020

Herein, we discuss a case of a 39-year-old male with hemophilia B, who developed end-stage liver disease secondary to nonalcoholic steatohepatitis, that underwent orthotopic liver transplantation (OLT) as a curative means for his liver disease and coagulation disorder. Existing case reports have demonstrated favorable outcomes in patients outside of the United States who received continuous infusions of recombinant factor IX replacement in the perioperative setting after liver transplant. Given limitations in the stability of the recombinant factor IX products in the United States, a dosing strategy was comprised of once daily bolus dosing to achieve satisfactory factor IX levels. Within 48 hours of initial surgery, the patient had sustained factor IX levels above 70% of normal and the patient required no further dosing of factor IX products to date. This strategy helped facilitate less frequent dosing as well as achieved targeted factor levels while synthetic function of the transplanted liver recovered.
Efficacy of Altered Two‐Point Fixation in Zygomaticomaxillary Complex Fracture
Authors: Kim Jun Hyeok , Kim Ye Sol , Oh Deuk Young , Jun Young Joon , Rhie Jong Won , Moon Suk-Ho
Published: March 2020

Purpose. To reconstruct a zygomaticomaxillary complex (ZMC) fracture, zygomaticofrontal (ZF) suture is the most reliable site to assess anatomical alignment and to secure rigidity. It has been chosen primary site to be fixed, but approach through the lateral eyebrow incision may leave a visible scar. This study suggests altered two‐point fixation of ZMC fracture without accessing the ZF suture. Methods. In the retrospective study, a total of 40 patients with ZMC fracture were divided into two groups (group 1, two‐point fixation and group 2, three‐point fixation). Patient demographics and follow‐up were evaluated, and degree of reduction including cortical gaps of ZF and inferior orbital (IO) area, protruding difference of zygoma, and malar difference using asymmetry index were measured through preoperative and postoperative CT. Results. Preoperatively, the means of ZF displacement, IO displacement, protruding difference of zygoma, and facial asymmetry index between the groups were not statistically different. The result was the same after the operation. However, all variables were significantly different before and after surgery within each group. Moreover, mean operation time was significantly different between groups (P value = 0.026). Conclusion. Altered two‐point fixation in ZMC fracture excluding incision approaching the ZF provides surgical efficacy and similar surgical outcomes to three‐point fixation but offers reduced operation time and fewer complications.
Simultaneous Quantitative Determination of Polyphenolic Compounds in Blumea balsamifera (Ai-Na-Xiang, Sembung) by High-Performance Liquid Chromatography with Photodiode Array Detector
Authors: Tan Daopeng , Yang Zhou , Zhang Qianru , Ling Hua , Du Yimei , Lu Yanliu , Xie Tianpei , Zhou Xumei , Qin Lin , He Yuqi
Published: March 2020

A high-performance liquid chromatography method was developed for simultaneous quantification of 18 polyphenolic compounds from the leaves of Blumea balsamifera, including 17 flavonoids and 1 phenylethanone. The B. balsamifera extraction was separated by a Kromasil C18 column (250 × 4.6 mm, 5 μm) with a binary gradient mobile phase consisting of acetonitrile and 0.2% aqueous acetic acid. A photodiode array detector (PDA) was used to record the signals of investigated constituents. The linearity, sensitivity, stability, precision, and accuracy of the established assay methods were assessed to meet the requirements of quantitative determination. Samples extracted by reflux in 25 mL of 80% methanol for 30 minutes were selected for the extraction method. The 18 compounds were accurately identified by comparing with the reference compounds. The purity of each peak was confirmed by the base peak in the mass spectrum. The contents of 18 compounds in Blumea samples from four different regions were successfully determined. The results also showed that 3,3′,5,7-tetrahydroxy-4′-methoxyflavanone was the most abundant constituent, which could be used as a potential chemical marker for quality control of B. balsamifera and Chinese patent medications containing B. balsamifera herb.
Bone Health in Premenopausal Chinese Patients after Adjuvant Chemotherapy for Early Breast Cancer
Authors: Yip Claudia H.W. , Liem Giok S. , Mo Frankie K.F. , Pang Elizabeth , Lei Yuan-yuan , Li Leung , Yip Christopher C.H. , Koh Jane , Ng Rita Y.W. , Suen Joyce J.S. , Yeo Winnie
Published: March 2020

Background: In this cohort study, the objectives were to determine bone mineral density (BMD) and potential associated factors for bone health among young premenopausal patients after adjuvant chemotherapy. Methods: Eligibility criteria included premenopausal Chinese aged <45 years who had received adjuvant chemotherapy. At study entry, background demographics and menstrual history were collected; BMD was measured. Factors associated with reduced BMD and fracture risk were analyzed. Results: A total of 271 patients entered the study. The median time from breast cancer diagnosis to study entry was 5.0 years. The median ages at breast cancer diagnosis and at study entry were 41 and 47 years, respectively. The median BMDs for femoral neck (FN) and lumbar spine (LS) were 0.72 and 0.91 g/cm2, respectively; 40.2% had abnormal Z-scores (defined as ≤–1) and 50.2% had osteopenia/osteoporosis of either FN or LS. On multivariate analyses, factors that were identified to have a positive association with bone health (higher BMD) included higher family income (OR [95% CI] for LS = 1.573 [1.091–2.268]), taller stature (OR for LS = 2.975 [1.723–5.137]), and higher BMI (OR for FN = 2.156 [1.599–2.907]), while negatively associated factors included longer interval since last adjuvant treatment (OR for LS: 0.435 [0.250–0.757]), peri-/postmenopausal status at study entry (OR for LS = 0.443 [0.255–0.768]; OR for FN = 0.353 [0.205–0.609]), and having received adjuvant tamoxifen (OR for FN = 0.452 [0.243–0.841]). Conclusion: About 5 years after breast cancer diagnosis and adjuvant chemotherapy, >50% of premenopausal patients who had received adjuvant chemotherapy were detected to have osteopenia/osteoporosis and 40% had abnormal Z-scores for FN/LS.
IgA Nephropathy Recurrence after Kidney Transplantation: Role of Recipient Age and Human Leukocyte Antigen-B Mismatch
Authors: Rodas Lida M. , Ruiz-Ortiz Estibaliz , Garcia-Herrera Adriana , Pereira Arturo , Blasco Miquel , Ventura-Aguiar Pedro , Viñas Gomis Odette , Egri Natalia , De Sousa Erika , Palou Eduard , Diekmann Fritz , Poch Esteban , Campistol Josep M. , Quintana Luis Fernando
Published: March 2020

Background: Recurrence of immunoglobulin (Ig)A nephropathy (rIgAN) is a growing cause of kidney allograft dysfunction. This study was aimed at investigating factors associated with rIgAN and the subsequent progression to end-stage renal disease (ESRD). Methods: Retrospective study including consecutive patients with IgA nephropathy (IgAN) who received a kidney transplant in our center between 1992 and 2016 and had a renal biopsy by clinical indication. The date of detection of chronic kidney disease (CKD) 5 was used as renal outcome. Results: Eighty-six kidney transplants were performed in patients with IgAN, 38 (44%) were from living donors (related n = 26). rIgAN was diagnosed in 23 allografts (27%). Renal function and proteinuria at the end of the follow-up period were worst in the rIgAN patients compared to those without rIgAN (2.2 vs. 1.4 mg/dL, p = 0.014, and 1.16 vs. 0.49 g/day, p = 0.005, respectively). Risk of rIgAN and progression to CKD 5 decreased with patient’s age (hazard ratio [HR] 0.95, 95% CI 0.92–0.98, p = 0.002, and HR 0.97, 95% CI 0.83–0.97, p = 0.008 per year, respectively). Patients with rIgAN had a higher risk of progression to CKD 5 (HR 6.7, 95% CI 1.3–35.7, p = 0.025). Full donor-recipient mismatch in the human leukocyte antigen (HLA)-B loci decreased the risk of rIgAN (HR 0.22, 95% CI 0.06–0.76, p = 0.017). Conclusions: rIgAN was an independent risk factor for ESRD after renal allograft. Younger age increased the risk of rIgAN and CKD 5. Conversely, HLA-B mismatching was a potential protective factor for rIgAN of this glomerular disease.
Etv2
- and
Fli1
-Induced Vascular Progenitor Cells Enhance Functional Recovery in Ischemic Vascular Disease Model—Brief Report
Authors: Park Soo Yong , Lee Hyunah , Kwon Yang Woo , Park Myung Rae , Kim Jae Ho , Kim Jeong Beom
Published: March 2020

Objective:

Vascular progenitor cells (VPCs), which are able to differentiate into both endothelial cells and smooth muscle cells, have the potential for treatment of ischemic diseases. Generated by pluripotent stem cells, VPCs carry the risk of tumorigenicity in clinical application. This issue could be resolved by direct lineage conversion, the induction of functional cells from another lineage by using only lineage-restricted transcription factors. Here, we show that induced VPCs (iVPCs) can be generated from fibroblasts by ETS (E-twenty six) transcription factors,
Etv2
and
Fli1
.

Approach and Results:

Mouse fibroblasts were infected with lentivirus encoding
Etv2
and
Fli1
. Cell colonies appeared in
Fli1
- and
Etv2/Fli1
-infected groups and were mechanically picked. The identity of cell colonies was confirmed by proliferation assay and reverse-transcription polymerase chain reaction with vascular markers
. Etv2/Fli1
- infected cell colonies were sorted by CD144 (also known as CDH5, VE-cadherin). We defined that CD144-positive iVPCs maintained its own population and expanded stably at multiple passages. iVPCs could differentiate into functional endothelial cells and smooth muscle cells by a defined medium. The functionalities of iVPC-derived endothelial cells and smooth muscle cells were confirmed by analyzing LDL (low-density lipoprotein) uptake, carbachol-induced contraction, and tube formation in vitro. Transplantation of iVPCs into the ischemic hindlimb model enhanced blood flow without tumor formation in vivo. Human iVPCs were generated by human ETS transcription factors
ETV2
and
FLI1
.

Conclusions:

We demonstrate that ischemic disease curable iVPCs, which have self-renewal and bipotency, can be generated from mouse fibroblasts by enforced ETS family transcription factors,
Etv2
and
Fli1
expression. Our simple strategy opens insights into stem cell–based ischemic disease therapy.
Nascent HDL (High-Density Lipoprotein) Discs Carry Cholesterol to HDL Spheres
Authors: Navdaev Alexei V. , Sborgi Lorenzo , Wright Samuel D. , Didichenko Svetlana A.
Published: March 2020

Objective:

To characterize the fate of protein and lipid in nascent HDL (high-density lipoprotein) in plasma and explore the role of interaction between nascent HDL and mature HDL in promoting ABCA1 (ATP-binding cassette transporter 1)-dependent cholesterol efflux.

Approach and Results:

Two discoidal species, nascent HDL produced by RAW264.7 cells expressing ABCA1 (LpA-I [apo AI containing particles formed by incubating ABCA1-expressing cells with apo AI]), and CSL112, human apo AI (apolipoprotein AI) reconstituted with phospholipids, were used for in vitro incubations with human plasma or purified spherical plasma HDL. Fluorescent labeling and biotinylation of HDL were employed to follow the redistribution of cholesterol and apo AI, cholesterol efflux was measured using cholesterol-loaded cells. We show that both nascent LpA-I and CSL112 can rapidly fuse with spherical HDL. Redistribution of the apo AI molecules and cholesterol after particle fusion leads to the formation of (1) enlarged, remodeled, lipid-rich HDL particles carrying lipid and apo AI from LpA-I and (2) lipid-poor apo AI particles carrying apo AI from both discs and spheres. The interaction of discs and spheres led to a greater than additive elevation of ABCA1-dependent cholesterol efflux.

Conclusions:

These data demonstrate that although newly formed discs are relatively poor substrates for ABCA1, they can interact with spheres to produce lipid-poor apo AI, a much better substrate for ABCA1. Because the lipid-poor apo AI generated in this interaction can itself become discoid by the action of ABCA1, cycles of cholesterol efflux and disc-sphere fusion may result in net ABCA1-dependent transfer of cholesterol from cells to HDL spheres. This process may be of particular importance in atherosclerotic plaque where cholesterol acceptors may be limiting.
Cardiac Myosin Promotes Thrombin Generation and Coagulation In Vitro and In Vivo
Authors: Zilberman-Rudenko Jevgenia , Deguchi Hiroshi , Shukla Meenal , Oyama Yoshimasa , Orje Jennifer N. , Guo Zihan , Wyseure Tine , Mosnier Laurent O. , McCarty Owen J.T. , Ruggeri Zaverio M. , Eckle Tobias , Griffin John H.
Published: March 2020

Objective:

Cardiac myosin (CM) is structurally similar to skeletal muscle myosin, which has procoagulant activity. Here, we evaluated CM’s ex vivo, in vivo, and in vitro activities related to hemostasis and thrombosis.

Approach and Results:

Perfusion of fresh human blood over CM-coated surfaces caused thrombus formation and fibrin deposition. Addition of CM to blood passing over collagen-coated surfaces enhanced fibrin formation. In a murine ischemia/reperfusion injury model, exogenous CM, when administered intravenously, augmented myocardial infarction and troponin I release. In hemophilia A mice, intravenously administered CM reduced tail-cut-initiated bleeding. These data provide proof of concept for CM’s in vivo procoagulant properties. In vitro studies clarified some mechanisms for CM’s procoagulant properties. Thrombin generation assays showed that CM, like skeletal muscle myosin, enhanced thrombin generation in human platelet-rich and platelet-poor plasmas and also in mixtures of purified factors Xa, Va, and prothrombin. Binding studies showed that CM, like skeletal muscle myosin, directly binds factor Xa, supporting the concept that the CM surface is a site for prothrombinase assembly. In tPA (tissue-type plasminogen activator)-induced plasma clot lysis assays, CM was antifibrinolytic due to robust CM-dependent thrombin generation that enhanced activation of TAFI (thrombin activatable fibrinolysis inhibitor).

Conclusions:

CM in vitro is procoagulant and prothrombotic. CM in vivo can augment myocardial damage and can be prohemostatic in the presence of bleeding. CM’s procoagulant and antifibrinolytic activities likely involve, at least in part, its ability to bind factor Xa and enhance thrombin generation. Future work is needed to clarify CM’s pathophysiology and its mechanistic influences on hemostasis or thrombosis.
Reactive Sulfur Species
Authors: Kolluru Gopi K. , Shen Xinggui , Kevil Christopher G.
Published: March 2020

Hydrogen sulfide has emerged as an important gaseous signaling molecule and a regulator of critical biological processes. However, the physiological significance of hydrogen sulfide metabolites such as persulfides, polysulfides, and other reactive sulfur species (RSS) has only recently been appreciated. Emerging evidence suggests that these RSS molecules may have similar or divergent regulatory roles compared with hydrogen sulfide in various biological activities. However, the chemical nature of persulfides and polysulfides is complex and remains poorly understood within cardiovascular and other pathophysiological conditions. Recent reports suggest that RSS can be produced endogenously, with different forms having unique chemical properties and biological implications involving diverse cellular responses such as protein biosynthesis, cell-cell barrier functions, and mitochondrial bioenergetics. Enzymes of the transsulfuration pathway, CBS (cystathionine beta-synthase) and CSE (cystathionine gamma-lyase), may also produce RSS metabolites besides hydrogen sulfide. Moreover, CARSs (cysteinyl-tRNA synthetase) are also able to generate protein persulfides via cysteine persulfide (CysSSH) incorporation into nascently formed polypeptides suggesting a new biologically relevant amino acid. This brief review discusses the biochemical nature and potential roles of RSS, associated oxidative stress redox signaling, and future research opportunities in cardiovascular disease.
Lifestyle and Risk Factor Modification for Reduction of Atrial Fibrillation: A Scientific Statement From the American Heart Association
Authors: Chung Mina K. , Eckhardt Lee L. , Chen Lin Y. , Ahmed Haitham M. , Gopinathannair Rakesh , Joglar José A. , Noseworthy Peter A. , Pack Quinn R. , Sanders Prashanthan , Trulock Kevin M. ,   On behalf of the American Heart Association Electrocardiography and Arrhythmias Committee and Exercise, Cardiac Rehabilitation, and Secondary Prevention Committee of the Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; and Council on Lifestyle and Cardiometabolic Health
Published: March 2020

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is associated with substantial morbidity, mortality, and healthcare use. Great strides have been made in stroke prevention and rhythm control strategies, yet reducing the incidence of AF has been slowed by the increasing incidence and prevalence of AF risk factors, including obesity, physical inactivity, sleep apnea, diabetes mellitus, hypertension, and other modifiable lifestyle-related factors. Fortunately, many of these AF drivers are potentially reversible, and emerging evidence supports that addressing these modifiable risks may be effective for primary and secondary AF prevention. A structured, protocol-driven multidisciplinary approach to integrate lifestyle and risk factor management as an integral part of AF management may help in the prevention and treatment of AF. However, this aspect of AF management is currently underrecognized, underused, and understudied. The purpose of this American Heart Association scientific statement is to review the association of modifiable risk factors with AF and the effects of risk factor intervention. Implementation strategies, care pathways, and educational links for achieving impactful weight reduction, increased physical activity, and risk factor modification are included. Implications for clinical practice, gaps in knowledge, and future directions for the research community are highlighted.
Deep Phenotyping by Mass Cytometry and Single-Cell RNA-Sequencing Reveals LYN-Regulated Signaling Profiles Underlying Monocyte Subset Heterogeneity and Lifespan
Authors: Roberts Morgan E. , Barvalia Maunish , Silva Jessica A.F.D. , Cederberg Rachel A. , Chu William , Wong Amanda , Tai Daven C. , Chen Sam , Matos Israel , Priatel John J. , Cullis Pieter R. , Harder Kenneth W.
Published: March 2020

Rationale:

Monocytes are key effectors of the mononuclear phagocyte system, playing critical roles in regulating tissue homeostasis and coordinating inflammatory reactions, including those involved in chronic inflammatory diseases such as atherosclerosis. Monocytes have traditionally been divided into 2 major subsets termed conventional monocytes and patrolling monocytes (pMo) but recent systems immunology approaches have identified marked heterogeneity within these cells, and much of what regulates monocyte population homeostasis remains unknown. We and others have previously identified LYN tyrosine kinase as a key negative regulator of myeloid cell biology; however, LYN’s role in regulating specific monocyte subset homeostasis has not been investigated.

Objective:

We sought to comprehensively profile monocytes to elucidate the underlying heterogeneity within monocytes and dissect how
Lyn
deficiency affects monocyte subset composition, signaling, and gene expression. We further tested the biological significance of these findings in a model of atherosclerosis.

Methods and Results:

Mass cytometric analysis of monocyte subsets and signaling pathway activation patterns in conventional monocytes and pMos revealed distinct baseline signaling profiles and far greater heterogeneity than previously described.
Lyn
deficiency led to a selective expansion of pMos and alterations in specific signaling pathways within these cells, revealing a critical role for LYN in pMo physiology. LYN’s role in regulating pMos was cell-intrinsic and correlated with an increased circulating half-life of
Lyn
-deficient pMos. Furthermore, single-cell RNA sequencing revealed marked perturbations in the gene expression profiles of
Lyn
−/−
monocytes with upregulation of genes involved in pMo development, survival, and function.
Lyn
deficiency also led to a significant increase in aorta-associated pMos and protected
Ldlr
−/−
mice from high-fat diet–induced atherosclerosis.

Conclusions:

Together our data identify LYN as a key regulator of pMo development and a potential therapeutic target in inflammatory diseases regulated by pMos.
AAV Gene Therapy Prevents and Reverses Heart Failure in a Murine Knockout Model of Barth Syndrome
Authors: Wang Suya , Li Yifei , Xu Yang , Ma Qing , Lin Zhiqiang , Schlame Michael , Bezzerides Vassilios J. , Strathdee Douglas , Pu William T.
Published: March 2020

Rationale:

Barth syndrome is an X-linked cardiac and skeletal myopathy caused by mutation of the gene Tafazzin (
TAZ
). Currently, there is no targeted treatment for Barth syndrome. Lack of a proper genetic animal model that recapitulates the features of Barth syndrome has hindered understanding of disease pathogenesis and therapeutic development.

Objective:

We characterized murine germline
TAZ
knockout mice (TAZ-KO) and cardiomyocyte-specific
TAZ
knockout mice models and tested the efficacy of adeno-associated virus (AAV)-mediated gene replacement therapy with human
TAZ
(hTAZ).

Methods and Results:

TAZ-KO caused embryonic and neonatal lethality, impaired growth, dilated cardiomyopathy, and skeletal myopathy. TAZ-KO mice that survived the neonatal period developed progressive, severe cardiac dysfunction, and fibrosis. Cardiomyocyte-specific inactivation of floxed
Taz
in cardiomyocytes using
Myh6-Cre
caused progressive dilated cardiomyopathy without fetal or perinatal loss. Using both constitutive and conditional knockout models, we tested the efficacy and durability of
Taz
replacement by
AAV
gene therapy. Neonatal AAV-hTAZ rescued neonatal death, cardiac dysfunction, and fibrosis in TAZ-KO mice, and both prevented and reversed established cardiac dysfunction in TAZ-KO and cardiomyocyte-specific
TAZ
knockout mice models. However, both neonatal and adult therapies required high cardiomyocyte transduction (≈70%) for durable efficacy.

Conclusions:

TAZ-KO and cardiomyocyte-specific
TAZ
knockout mice recapitulate many of the key clinical features of Barth syndrome. AAV-mediated gene replacement is efficacious when a sufficient fraction of cardiomyocytes are transduced.
Atherogenic Lipoprotein(a) Increases Vascular Glycolysis, Thereby Facilitating Inflammation and Leukocyte Extravasation
Authors: Schnitzler Johan G. , Hoogeveen Renate M. , Ali Lubna , Prange Koen H.M. , Waissi Farahnaz , van Weeghel Michel , Bachmann Julian C. , Versloot Miranda , Borrelli Matthew J. , Yeang Calvin , De Kleijn Dominique P.V. , Houtkooper Riekelt H. , Koschinsky Marlys L. , de Winther Menno P.J. , Groen Albert K. , Witztum Joseph L. , Tsimikas Sotirios , Stroes Erik S.G. , Kroon Jeffrey
Published: March 2020

Rationale:

Patients with elevated levels of lipoprotein(a) [Lp(a)] are hallmarked by increased metabolic activity in the arterial wall on positron emission tomography/computed tomography, indicative of a proinflammatory state.

Objective:

We hypothesized that Lp(a) induces endothelial cell inflammation by rewiring endothelial metabolism.

Methods and Results:

We evaluated the impact of Lp(a) on the endothelium and describe that Lp(a), through its oxidized phospholipid content, activates arterial endothelial cells, facilitating increased transendothelial migration of monocytes. Transcriptome analysis of Lp(a)-stimulated human arterial endothelial cells revealed upregulation of inflammatory pathways comprising monocyte adhesion and migration, coinciding with increased 6-phophofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)-3–mediated glycolysis. ICAM (intercellular adhesion molecule)-1 and PFKFB3 were also found to be upregulated in carotid plaques of patients with elevated levels of Lp(a). Inhibition of PFKFB3 abolished the inflammatory signature with concomitant attenuation of transendothelial migration.

Conclusions:

Collectively, our findings show that Lp(a) activates the endothelium by enhancing PFKFB3-mediated glycolysis, leading to a proadhesive state, which can be reversed by inhibition of glycolysis. These findings pave the way for therapeutic agents targeting metabolism aimed at reducing inflammation in patients with cardiovascular disease.
A Computational Pipeline to Predict Cardiotoxicity
Authors: Yang Pei-Chi , DeMarco Kevin R. , Aghasafari Parya , Jeng Mao-Tsuen , Dawson John R.D. , Bekker Slava , Noskov Sergei Y. , Yarov-Yarovoy Vladimir , Vorobyov Igor , Clancy Colleen E.
Published: March 2020

Rationale:

Drug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that QT prolongation is an accepted surrogate marker for arrhythmia. But QT interval is too sensitive a marker and not selective, resulting in many useful drugs eliminated in drug discovery.

Objective:

To predict the impact of a drug from the drug chemistry on the cardiac rhythm.

Methods and Results:

In a new linkage, we connected atomistic scale information to protein, cell, and tissue scales by predicting drug-binding affinities and rates from simulation of ion channel and drug structure interactions and then used these values to model drug effects on the hERG channel. Model components were integrated into predictive models at the cell and tissue scales to expose fundamental arrhythmia vulnerability mechanisms and complex interactions underlying emergent behaviors. Human clinical data were used for model framework validation and showed excellent agreement, demonstrating feasibility of a new approach for cardiotoxicity prediction.

Conclusions:

We present a multiscale model framework to predict electrotoxicity in the heart from the atom to the rhythm. Novel mechanistic insights emerged at all scales of the system, from the specific nature of proarrhythmic drug interaction with the hERG channel, to the fundamental cellular and tissue-level arrhythmia mechanisms. Applications of machine learning indicate necessary and sufficient parameters that predict arrhythmia vulnerability. We expect that the model framework may be expanded to make an impact in drug discovery, drug safety screening for a variety of compounds and targets, and in a variety of regulatory processes.
Integrin β1D Deficiency–Mediated RyR2 Dysfunction Contributes to Catecholamine-Sensitive Ventricular Tachycardia in Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Wang Yihui , Li Chunyan , Shi Ling , Chen Xiuyu , Cui Chen , Huang Jinhua , Chen Biyi , Hall Duane D. , Pan Zhenwei , Lu Minjie , Hong Jiang , Song Long-Sheng , Zhao Shihua
Published: March 2020

Background:

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary heart disease characterized by fatty infiltration, life-threatening arrhythmias, and increased risk of sudden cardiac death. The guideline for management of ARVC in patients is to improve quality of life by reducing arrhythmic symptoms and to prevent sudden cardiac death. However, the mechanism underlying ARVC-associated cardiac arrhythmias remains poorly understood.

Methods:

Using protein mass spectrometry analyses, we identified that integrin β1 is downregulated in ARVC hearts without changes to Ca
2+
-handling proteins. As adult cardiomyocytes express only the β1D isoform, we generated a cardiac specific β1D knockout mouse model and performed functional imaging and biochemical analyses to determine the consequences of integrin β1D loss on function in the heart in vivo and in vitro.

Results:

Integrin β1D deficiency and RyR2 Ser-2030 hyperphosphorylation were detected by Western blotting in left ventricular tissues from patients with ARVC but not in patients with ischemic or hypertrophic cardiomyopathy. Using lipid bilayer patch clamp single channel recordings, we found that purified integrin β1D protein could stabilize RyR2 function by decreasing RyR2 open probability, mean open time, and increasing mean close time. Also, β1D knockout mice exhibited normal cardiac function and morphology but presented with catecholamine-sensitive polymorphic ventricular tachycardia, consistent with increased RyR2 Ser-2030 phosphorylation and aberrant Ca
2+
handling in β1D knockout cardiomyocytes. Mechanistically, we revealed that loss of DSP (desmoplakin) induces integrin β1D deficiency in ARVC mediated through an ERK1/2 (extracellular signal–regulated kinase 1 and 2)–fibronectin–ubiquitin/lysosome pathway.

Conclusions:

Our data suggest that integrin β1D deficiency represents a novel mechanism underlying the increased risk of ventricular arrhythmias in patients with ARVC.
Role of Deranged Energy Deprivation Signaling in the Pathogenesis of Cardiac and Renal Disease in States of Perceived Nutrient Overabundance
Authors: Packer Milton
Published: March 2020

Sodium-glucose cotransporter 2 inhibitors reduce the risk of serious heart failure and adverse renal events, but the mechanisms that underlie this benefit are not understood. Treatment with SGLT2 inhibitors is distinguished by 2 intriguing features: ketogenesis and erythrocytosis. Both reflect the induction of a fasting-like and hypoxia-like transcriptional paradigm that is capable of restoring and maintaining cellular homeostasis and survival. In the face of perceived nutrient and oxygen deprivation, cells activate low-energy sensors, which include sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia inducible factors (HIFs; especially HIF-2α); these enzymes and transcription factors are master regulators of hundreds of genes and proteins that maintain cellular homeostasis. The activation of SIRT1 (through its effects to promote gluconeogenesis and fatty acid oxidation) drives ketogenesis, and working in concert with AMPK, it can directly inhibit inflammasome activation and maintain mitochondrial capacity and stability. HIFs act to promote oxygen delivery (by stimulating erythropoietin and erythrocytosis) and decrease oxygen consumption. The activation of SIRT1, AMPK, and HIF-2α enhances autophagy, a lysosome-dependent degradative pathway that removes dangerous constituents, particularly damaged mitochondria and peroxisomes, which are major sources of oxidative stress and triggers of cellular dysfunction and death. SIRT1 and AMPK also act on sodium transport mechanisms to reduce intracellular sodium concentrations. It is interesting that type 2 diabetes mellitus, obesity, chronic heart failure, and chronic kidney failure are characterized by the accumulation of intracellular glucose and lipid intermediates that are perceived by cells as indicators of energy overabundance. The cells respond by downregulating SIRT1, AMPK, and HIF-2α, thus leading to an impairment of autophagic flux and acceleration of cardiomyopathy and nephropathy. SGLT2 inhibitors reverse this maladaptive signaling by triggering a state of fasting and hypoxia mimicry, which includes activation of SIRT1, AMPK, and HIF-2α, enhanced autophagic flux, reduced cellular stress, decreased sodium influx into cells, and restoration of mitochondrial homeostasis. This mechanistic framework clarifies the findings of large-scale randomized trials and the close association of ketogenesis and erythrocytosis with the cardioprotective and renoprotective benefits of these drugs.
Endothelial Sphingolipid De Novo Synthesis Controls Blood Pressure by Regulating Signal Transduction and NO via Ceramide
Authors: Cantalupo Anna , Sasset Linda , Gargiulo Antonella , Rubinelli Luisa , Del Gaudio Ilaria , Benvenuto Domenico , Wadsack Christian , Jiang Xiang-Chen , Bucci Maria Rosaria , Di Lorenzo Annarita
Published: March 2020

Ceramides are sphingolipids that modulate a variety of cellular processes via 2 major mechanisms: functioning as second messengers and regulating membrane biophysical properties, particularly lipid rafts, important signaling platforms. Altered sphingolipid levels have been implicated in many cardiovascular diseases, including hypertension, atherosclerosis, and diabetes mellitus–related conditions; however, molecular mechanisms by which ceramides impact endothelial functions remain poorly understood. In this regard, we generated mice defective of endothelial sphingolipid de novo biosynthesis by deleting the Sptlc2 (long chain subunit 2 of serine palmitoyltransferase)—the first enzyme of the pathway. Our study demonstrated that endothelial sphingolipid de novo production is necessary to regulate (1) signal transduction in response to NO agonists and, mainly via ceramides, (2) resting eNOS (endothelial NO synthase) phosphorylation, and (3) blood pressure homeostasis. Specifically, our findings suggest a prevailing role of C16:0-Cer in preserving vasodilation induced by tyrosine kinase and GPCRs (G-protein coupled receptors), except for Gq-coupled receptors, while C24:0- and C24:1-Cer control flow-induced vasodilation. Replenishing C16:0-Cer in vitro and in vivo reinstates endothelial cell signaling and vascular tone regulation. This study reveals an important role of locally produced ceramides, particularly C16:0-, C24:0-, and C24:1-Cer in vascular and blood pressure homeostasis, and establishes the endothelium as a key source of plasma ceramides. Clinically, specific plasma ceramides ratios are independent predictors of major cardiovascular events. Our data also suggest that plasma ceramides might be indicative of the diseased state of the endothelium.
Effect of Steady and Dynamic Blood Pressure Parameters During Thrombectomy According to the Collateral Status
Authors: Maïer Benjamin , Dargazanli Cyril , Bourcier Romain , Kyheng Maëva , Labreuche Julien , Mosimann Pascal J. , Puccinelli Francesco , Taylor Guillaume , Le Guen Morgan , Riem Romuald , Desilles Jean-Philippe , Boisseau William , Fahed Robert , Redjem Hocine , Smajda Stanislas , Ciccio Gabriele , Escalard Simon , Blanc Raphaël , Piotin Michel , Lapergue Betrand , Mazighi Mikael ,   on behalf of the ASTER Trial
Published: March 2020

Background and Purpose—

Guidelines regarding blood pressure (BP) management during endovascular therapy (EVT) for anterior circulation strokes are questionable since the optimal BP target is a matter of debate. To evaluate the importance of hemodynamic control during EVT, we investigated the impact of dynamic and steady BP parameters during EVT on functional outcome (part 1) and according to the collateral status (CS; part 2).

Methods—

We performed a post hoc analysis of the ASTER trial (Contact Aspiration Versus Stent Retriever for Successful Recanalization). BP was measured noninvasively during EVT and CS assessed on the angiographic run before EVT. We studied dynamic BP parameter using BP variability (coefficient of variation) and steady BP parameter (hypotension time defined as systolic BP <140 mm Hg and mean arterial pressure <90 mm Hg). The primary outcome was favorable outcome defined as a 3-month modified Rankin Scale score between 0 and 2.

Results—

Among the 381 patients of the ASTER study, 172 patients were included in part 1 and 159 in part 2. Systolic BP, diastolic BP, and mean arterial pressure variability were negatively associated with favorable outcome regardless of CS: per 10-unit increase, adjusted odds ratios were 0.45 (95% CI, 0.20–0.98), 0.37 (95% CI, 0.19–0.72), and 0.35 (95% CI, 0.16–0.76), respectively. According to CS, the hypotension time with periprocedural mean arterial pressure <90 mm Hg was negatively associated with favorable outcome in patients with poor CS (adjusted odds ratio, 0.88 [95% CI, 0.72–1.09]) but not in patients with good CS (adjusted odds ratio, 1.24 [95% CI, 0.91–1.67];
P
het
=0.047).

Conclusions—

The CS did not modify the association between dynamic parameters and functional outcomes, but some findings suggest that the CS modifies the association between steady parameter and functional outcomes. Hypotension time according to the CS was not statistically predictive of poor outcomes but displayed a trend toward worse outcomes for patients with poor CS only.
Electrocardiographic ST-T Abnormities Are Associated With Stroke Risk in the REGARDS Study
Authors: Sawano Mitsuaki , Yuan Ya , Kohsaka Shun , Inohara Taku , Suzuki Takeki , Okamura Tomonori , Howard George , Howard Virginia J. , Judd Suzanne , Soliman Elsayed Z. , Cushman Mary
Published: March 2020

Background and Purpose—

In previous studies, isolated nonspecific ST-segment and T-wave abnormalities (NSSTTAs), a common finding on ECGs, were associated with greater risk for incident coronary artery disease. Their association with incident stroke remains unclear.

Methods—

The REGARDS (Reasons for Geographic and Racial Differences in Stroke) study is a population-based, longitudinal study of 30 239 white and black adults enrolled from 2003 to 2007 in the United States. NSSTTAs were defined from baseline ECG using the standards of Minnesota ECG Classification (Minnesota codes 4-3, 4-4, 5-3, or 5-4). Participants with prior stroke, coronary heart disease, and major and minor ECG abnormalities other than NSSTTAs were excluded from analysis. Multivariable Cox proportional hazards regression was used to examine calculate hazard ratios of incident ischemic stroke by presence of baseline NSSTTAs.

Results—

Among 14 077 participants, 3111 (22.1%) had NSSTTAs at baseline. With a median of 9.6 years follow-up, 106 (3.4%) with NSSTTAs had ischemic stroke compared with 258 (2.4%) without NSSTTAs. The age-adjusted incidence rates (per 1000 person-years) of stroke were 2.93 in those with NSSTTAs and 2.19 in those without them. Adjusting for baseline age, sex, race, geographic location, and education level, isolated NSSTTAs were associated with a 32% higher risk of ischemic stroke (hazard ratio, 1.32 [95% CI, 1.05–1.67]). With additional adjustment for stroke risk factors, the risk of stroke was increased 27% (hazard ratio, 1.27 [95% CI, 1.00–1.62]) and did not differ by age, race, or sex.

Conclusions—

Presence of NSSTTAs in persons with an otherwise normal ECG was associated with a 27% increased risk of future ischemic stroke.
Bone Marrow Mononuclear Cells Activate Angiogenesis via Gap Junction–Mediated Cell-Cell Interaction
Authors: Kikuchi-Taura Akie , Okinaka Yuka , Takeuchi Yukiko , Ogawa Yuko , Maeda Mitsuyo , Kataoka Yosky , Yasui Teruhito , Kimura Takafumi , Gul Sheraz , Claussen Carsten , Boltze Johannes , Taguchi Akihiko
Published: March 2020

Background and Purpose—

Bone marrow mononuclear cells (BM-MNCs) are a rich source of hematopoietic stem cells and have been widely used in experimental therapies for patients with ischemic diseases. Activation of angiogenesis is believed to be one of major BM-MNC mode of actions, but the essential mechanism by which BM-MNCs activate angiogenesis have hitherto been elusive. The objective of this study is to reveal the mechanism how BM-MNCs activate angiogenesis.

Methods—

We have evaluated the effect of direct cell-cell interaction between BM-MNC and endothelial cell on uptake of VEGF (vascular endothelial growth factor) into endothelial cells in vitro. Cerebral ischemia model was used to evaluate the effects of direct cell-cell interaction with transplanted BM-MNC on endothelial cell at ischemic tissue.

Results—

The uptake of VEGF into endothelial cells was increased by BM-MNC, while being inhibited by blockading the gap junction. Low-molecular-weight substance was transferred from BM-MNC into endothelial cells via gap junctions in vivo, followed by increased expression of hypoxia-inducible factor-1α and suppression of autophagy in endothelial cells. The concentration of glucose in BM-MNC cytoplasm was significantly higher than in endothelial cells, and transfer of glucose homologue from BM-MNC to endothelial cells was observed.

Conclusions—

Our findings demonstrated cell-cell interaction via gap junction is the prominent pathway for activation of angiogenesis at endothelial cells after ischemia and provided novel paradigm that energy source supply by stem cell to injured cell is one of the therapeutic mechanisms of cell-based therapy.

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