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  • Cocoa to Improve Walking Performance in Older People With Peripheral Artery Disease: The Cocoa-Pad Pilot Randomized Clinical Trial
    Circ. Res. (IF 15.862) Pub Date : 2020-02-14
    Mary M. McDermott; Michael H Criqui; Kathryn Domanchuk; Luigi Ferrucci; Jack M Guralnik; Melina Kibbe; Kate Kosmac; Christopher M Kramer; Christiaan Leeuwenburgh; Lingyu Li; Donald M. Lloyd-Jones; Charlotte A Peterson; Tamar S Polonsky; James H Stein; Robert Sufit; Linda V Van Horn; Francisco J Villarreal; Dongxue Zhang; Lihui Zhao; Lu Tian

    Rationale: Cocoa and its major flavanol component, epicatechin, have therapeutic properties that may improve limb perfusion and increase calf muscle mitochondrial activity in people with lower extremity peripheral artery disease (PAD).Objective: In a phase II randomized clinical trial, to assess whether six months of cocoa improved walking performance in people with PAD, compared to placebo.Methods and Results: Six-month double blind randomized clinical trial in which participants with PAD were randomized to either cocoa beverage vs. placebo beverage. The cocoa beverage contained 15 grams of cocoa and 75 mgs of epicatechin daily. The identical appearing placebo contained neither cocoa nor epicatechin. The two primary outcomes were six-month change in six-minute walk distance measured 2.5 hours after a study beverage at 6-month follow-up and 24 hours after a study beverage at 6-month follow-up, respectively. A one-sided P value <0.10 was considered statistically significant. Of 44 PAD participants randomized (mean age: 72.3 years (+7.1), mean ankle brachial index 0.66 (+0.15)), 40 (91%) completed follow-up. Adjusting for smoking, race, and body mass index, cocoa improved six-minute walk distance at 6-month follow-up by 42.6 meters (90% Confidence Interval (CI): +22.2,+∞, P=0.005) at 2.5 hours after a final study beverage and by 18.0 meters (90% CI:-1.7, +∞, P=0.12) at 24 hours after a study beverage, compared to placebo. In calf muscle biopsies, cocoa improved mitochondrial cytochrome c oxidase activity (P=0.013), increased capillary density (P=0.014), improved calf muscle perfusion (P=0.098), and reduced central nuclei (P=0.024), compared to placebo.Conclusions: These preliminary results suggest a therapeutic effect of cocoa on walking performance in people with PAD. Further study is needed to definitively determine whether cocoa significantly improves walking performance in people with PAD. Clinical Trial Registration: NCT02876887.

    更新日期:2020-02-14
  • In This Issue
    Circ. Res. (IF 15.862) Pub Date : 2020-02-13
    Ruth Williams

    Hypertension, which affects approximately a third of the global adult population, is a risk factor for stroke, myocardial infarction, and heart failure. Although blood pressure-lowering treatments are widely available, in approximately one third of patients, the condition remains uncontrolled. A thorough understanding of the complex pathophysiology of the condition would facilitate the search for much needed alternative treatments. To that end, Dikalova and colleagues have investigated Sirt3, an enzyme that tends to be at lower-than-usual levels in patients with hypertension and that regulates metabolic and antioxidant functions—both of which, if disturbed, can contribute to vascular dysfunction. The team showed that mice genetically engineered to overexpress Sirt3 had healthier blood vessels and lower blood pressure than control animals when subjected to experimentally induced hypertension. By contrast, Sirt3 depletion was shown to cause vascular inflammation and increased signs of vascular aging in mice. The team also confirmed the link between low Sirt3 levels and hypertension in humans. It is not clear why Sirt3 levels are low in certain people, but nevertheless, the findings suggest that boosting this enzyme may be a potential therapy for hypertension, say the authors. The main energy source of the heart is fatty acid metabolism, but excessive lipids—resulting from diet-induced dyslipidemia, for example—can cause cardiomyocyte dysfunction. It’s known that lipid overload in the heart can cause increased activity of Drp1 (dynamin-related protein 1)—an enzyme that directs mitochondrial fission. But exactly how Drp1 becomes activated is unclear. In mice fed a high-fat diet, Hu and colleagues confirm that Drp1 activity and mitochondrial fission are abnormally increased, and that there are signs of heart dysfunction. They also show similar effects of a high-fat diet in monkeys. While levels of Drp1 mRNA were not altered in the mouse hearts, Drp1 protein acetylation was increased. The team went on to perform experiments on cultured rat cardiomyocytes, showing that incubation with the saturated fatty acid palmitate led to acetylation of Drp1 and thus its activation—resulting in excess mitochondrial fission and reduced cell viability. Mutation of Drp1 to prevent its acetlyation, by contrast, protected the cells. Together, the results reveal how dyslipidemia can contribute to heart cell dysfunction and suggest that Drp1 activity or acetylation state could be novel targets for treating obesity-related heart disease. During an infection or injury, blood vessels become leaky to allow white blood cells to reach the sites of invasion or damage. But in sepsis, this normal inflammatory response becomes excessive and can lead to organ failure and death. The blood factor thrombin is a driver of vessel endothelium permeability, acting through its receptor, PAR1 (protease-activated receptor 1), on endothelial cells. But downstream molecular details of thrombin-induced endothelial permeability are lacking. Now, Li and colleagues show that a protein called BMX (bone marrow kinase on the X chromosome), which is highly expressed in endothelial cells and was known to interact with PAR1, actively suppresses thrombin-induced permeability. Studying mice with and without BMX after experimentally induced sepsis, the team showed that a lack of BMX exacerbated the condition, increasing vessel leakage. They also showed in cultured cells that BMX repressed thrombin-PAR1 signaling by phosphorylating and internalizing the receptor causing its deactivation. Indeed, PAR1 inhibition could reduce endothelial permeability in the sepsis-stricken, BMX-lacking mice and improve their survival. These results suggest that boosting BMX could be a treatment strategy for excessive or uncontrolled vascular leakage.

    更新日期:2020-02-14
  • Meet the First Author
    Circ. Res. (IF 15.862) Pub Date : 2020-02-13

    Dr Xinyu Zhou graduated from Northwest University, Xi’an, China, with a BS in Biotechnology. In 2018, he earned his PhD at The Ohio State University under the mentorship of Dr Jianjie Ma. While studying for his PhD, he investigated the regulation of calcium signaling in cardiac muscle. Dr Zhou also specializes in imaging and molecular and biochemical tools for translational research in tissue repair and regeneration. Currently a postdoctoral researcher in Dr Ma’s lab, Xinyu is continuing his work to advance the understanding of calcium signaling regulation and explore the potential treatment of heart disease. Outside of the lab, Xinyu enjoys family time with his wife and two children. He likes reading, photography, sports, and traveling. Dr Ki Ho Park earned his BS in electrical engineering and a PhD in system engineering from the University of Tokushima, Japan. While studying the effects of electromagnetic fields on cells in his PhD program, his interest shifted from engineering to life sciences. He studied ion channels during his first postdoctoral fellowship at the Rutgers University Robert Wood Johnson Medical School, gaining extensive knowledge and skills in molecular biology, biochemistry, and electrophysiology. After joining Dr Jianjie Ma’s laboratory, he currently explores the role of proteins that regulate calcium signaling under cardiac stress or inflammation by using in vitro and in vivo imaging techniques. In his spare time, he loves watching movies and spending time with his family and friends. Dr Qingxun Hu earned his MS in Biochemistry and Molecular Biology in Dr Yi Yang’s lab at East China University of Science and Technology, where his work focused on the development of biosensors for intracellular NAD(H) signals, including SoNar, FiNad, and Frex. He earned his PhD in Dr Yi Zhun Zhu’s lab at Fudan University, where he developed a novel H2S and NO conjugated donor for cardiovascular protection. Currently, his research focuses on mitochondrial dynamics, redox regulation, and protein modification in metabolic heart disease. He is also interested in dissecting compartmentalized NAD+/NADH ratios in live cells. He enjoys soccer and hiking with his beloved daughter and wife. Dr Zhao Li earned his BS in Bioengineering and an MS in Pathology and Pathophysiology from Xi’an Jiaotong University, China. In 2017, he completed his PhD, also from Xi’an Jiaotong University. He is currently a postdoctoral fellow at The Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University. His research interests include endothelial dysfunction diseases, endothelial homeostasis and vascular remodelling, and the communication between lipid metabolism and endothelial function. While studying the mechanism in early sepsis and the possible treatments for it, he and his coauthors found that endothelial permeability and vascular leakage participate in early sepsis while maintaining endothelial function. Dr Mingzhu Yin is a Professor and Co-Director of Dermatology at the Xiangya Hospital, Central South University, China. He earned his MD in Oncology from the Harbin Medical University in 2008 and his PhD in Integrated Traditional Chinese and Western Medicine from the China Pharmaceutical University (CPU) with Yale University Combined Training in 2015. He joined the Harbin Medical University as a Clinical Doctor in 2011 and the National Institute on Aging (NIA/NIH) as a Postdoctoral Scholar in 2012. Dr Yin’s research interests include the application of immune cell and microvessels to regulate transcoelomic, lymphatic and vascular metastasis of cancer. Dr Tobias Petzold is currently working as an Associate Professor in the Department of Cardiology at Ludwig-Maximilian University (LMU) in Munich. In addition to his MD from LMU, he earned an MS in Biomedical Science from the University of Virginia. During his doctoral thesis at the Max-Planck- Institute for Biochemistry in Martinsried (mentor, Dr Reinhard Fässler), he investigated the mechanisms of platelet integrin activation. He completed his clinical training and postdoctoral studies under the supervision of. Dr Steffen Massberg at LMU. His research focuses on the mechanisms of platelet activation during thrombosis and novel antithrombotic therapies. At the 2017 meeting of the German Cardiac Society, Tobias Petzold and Amin Polzin decided to conduct their recent multicentric translational study. Outside of work, he enjoys spending time with his family in the mountains. Dr Amin Polzin is an Associate Professor in the Department of Cardiology, Pneumology and Vascular Medicine of the University Hospital Düsseldorf (mentor, Dr Malte Kelm). As a clinical physician, he combines deep passion for interventional cardiology and science. Under the profound supervision of Dr Kelm, he was trained in clinical, translational and basic science. He extended his skills during research fellowships in the Institute of Pharmacology and Clinical Pharmacology at the Heinrich Heine University Düsseldorf and Institute of Pathophysiology in Essen. After working separately on similar projects regarding Factor IIa inhibition, Amin Polzin and Tobias Petzold joined forces on the present project to identify the role of Factor Xa in platelet activation. Dr Manabu Nagao is an assistant professor at Kobe University in Japan. He earned his MD from Mie University School of Medicine and completed his PhD at Kobe University. Dr Nagao then joined the laboratory of Tom Quertermous at Stanford University as a postdoctoral scholar and investigated the molecular mechanisms behind genetic risk factors for human cardiovascular disease, especially focusing on vascular smooth muscle cells. Now, his interests are in cardiac metabolism under pathological conditions, including cardiac ischemia and diabetes. To gain further insights, he now devotes his research to studies in this field. Outside of the lab, he enjoys watching Sumo on TV.

    更新日期:2020-02-14
  • TRIC-A Channel Maintains Store Calcium Handling by Interacting with Type 2 Ryanodine Receptor in Cardiac Muscle.
    Circ. Res. (IF 15.862) Pub Date : 2019
    Xinyu Zhou,Ki Ho Park,Daiju Yamazaki,Peihui Lin,Miyuki Nishi,Zhiwei Ma,Liming Qiu,Takashi Murayama,Xiaoqin Zou,Hiroshi Takeshima,Jingsong Zhou,Jianjie Ma

    Rationale: TRIC-A and TRIC-B are distributed to endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR) intracellular Ca2+ stores. The crystal structure of TRIC has been determined, confirming the homo-trimeric structure of a potassium channel. While the pore architectures of TRIC-A and TRIC-B are conserved, the carboxyl-terminal tail domains (CTT) of TRIC-A and TRIC-B are different from each other. Aside from its recognized role as a counter-ion channel that participates in excitation-contraction coupling of striated muscles, the physiological function of TRIC-A in heart physiology and disease has remained largely unexplored. Objective: In cardiomyocytes, spontaneous Ca2+ waves, triggered by store overload-induced Ca2+ release (SOICR) mediated by the type 2 ryanodine receptor (RyR2), develop extra-systolic contractions often associated with arrhythmic events. Here we test the hypothesis that TRIC-A is a physiologic component of RyR2-mediated Ca2+ release machinery that directly modulates SOICR activity via CTT. Methods and Results: We show that cardiomyocytes derived from the TRIC-A-/- mice display dysregulated Ca2+ movement across SR. Biochemical studies demonstrate a direct interaction between CTT-A and RyR2. Modeling and docking studies reveal potential sites on RyR2 that show differential interactions with CTT-A and CTT-B. In HEK293 cells with stable expression of RyR2, transient expression of TRIC-A, but not TRIC-B, leads to apparent suppression of spontaneous Ca2+ oscillations. Ca2+ measurements using the cytosolic indicator Fura-2 and the ER luminal store indicator D1ER suggest that TRIC-A enhances Ca2+ leak across the ER by directly targeting RyR2 to modulate SOICR. Moreover, synthetic CTT-A peptide facilitates RyR2 activity in lipid bilayer reconstitution system, enhances Ca2+ sparks in permeabilized TRIC-A-/- cardiomyocytes, and induces intracellular Ca2+ release after micro-injection into isolated cardiomyocytes, whereas such effects were not observed with the CTT-B peptide. In response to isoproterenol stimulation, the TRIC-A-/- mice display irregular electrocardiogram and develop more fibrosis than the WT littermates. Conclusions: In addition to the ion-conducting function, TRIC-A functions as an accessory protein of RyR2 to modulate SR Ca2+ handling in cardiac muscle.

    更新日期:2020-02-14
  • Mitochondrial Deacetylase Sirt3 Reduces Vascular Dysfunction and Hypertension While Sirt3 Depletion in Essential Hypertension Is Linked to Vascular Inflammation and Oxidative Stress
    Circ. Res. (IF 15.862) Pub Date : 2019-12-19
    Anna E. Dikalova; Arvind Pandey; Liang Xiao; Liaisan Arslanbaeva; Tatiana Sidorova; Marcos G. Lopez; Frederic T. Billings IV; Eric Verdin; Johan Auwerx; David G. Harrison; Sergey I. Dikalov

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    更新日期:2020-02-14
  • Increased Drp1 Acetylation by Lipid Overload Induces Cardiomyocyte Death and Heart Dysfunction
    Circ. Res. (IF 15.862) Pub Date : 2020-01-03
    Qingxun Hu; Huiliang Zhang; Nicolás Gutiérrez Cortés; Dan Wu; Pei Wang; Jing Zhang; Julie A. Mattison; Eric Smith; Lisa F. Bettcher; Mingyi Wang; Edward G. Lakatta; Shey-Shing Sheu; Wang Wang

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    更新日期:2020-02-14
  • BMX Represses Thrombin-PAR1–Mediated Endothelial Permeability and Vascular Leakage During Early Sepsis
    Circ. Res. (IF 15.862) Pub Date : 2020-01-08
    Zhao Li; Mingzhu Yin; Haifeng Zhang; Weiming Ni; Richard W. Pierce; Huanjiao Jenny Zhou; Wang Min

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    更新日期:2020-02-14
  • Rivaroxaban Reduces Arterial Thrombosis by Inhibition of FXa-Driven Platelet Activation via Protease Activated Receptor-1
    Circ. Res. (IF 15.862) Pub Date : 2019-12-20
    Tobias Petzold; Manuela Thienel; Lisa Dannenberg; Philipp Mourikis; Carolin Helten; Aysel Ayhan; René M’Pembele; Alina Achilles; Kajetan Trojovky; Daniel Konsek; Zhe Zhang; Ron Regenauer; Joachim Pircher; Andreas Ehrlich; Enzo Lüsebrink; Leo Nicolai; Thomas J. Stocker; Richard Brandl; Franz Röschenthaler; Jan Strecker; Inas Saleh; Michael Spannagl; Christoph H. Mayr; Herbert B. Schiller; Christian Jung; Norbert Gerdes; Till Hoffmann; Bodo Levkau; Thomas Hohlfeld; Tobias Zeus; Christian Schulz; Malte Kelm; Amin Polzin

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    更新日期:2020-02-14
  • Longitudinal RNA-Seq Analysis of the Repeatability of Gene Expression and Splicing in Human Platelets Identifies a Platelet SELP Splice QTL
    Circ. Res. (IF 15.862) Pub Date : 2019-12-19
    Matthew T. Rondina; Deepak Voora; Lukas M. Simon; Hansjörg Schwertz; Julie F. Harper; Olivia Lee; Seema C. Bhatlekar; Qing Li; Alicia S. Eustes; Emilie Montenont; Robert A. Campbell; Neal D. Tolley; Yasuhiro Kosaka; Andrew S. Weyrich; Paul F. Bray; Jesse W. Rowley

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    更新日期:2020-02-14
  • Coronary Disease-Associated Gene TCF21 Inhibits Smooth Muscle Cell Differentiation by Blocking the Myocardin-Serum Response Factor Pathway
    Circ. Res. (IF 15.862) Pub Date : 2019-12-09
    Manabu Nagao; Qing Lyu; Quanyi Zhao; Robert C. Wirka; Joetsaroop Bagga; Trieu Nguyen; Paul Cheng; Juyong Brian Kim; Milos Pjanic; Joseph M. Miano; Thomas Quertermous

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    更新日期:2020-02-14
  • Targeting Age-Related Pathways in Heart Failure
    Circ. Res. (IF 15.862) Pub Date : 2020-02-13
    Haobo Li; Margaret H. Hastings; James Rhee; Lena E. Trager; Jason D. Roh; Anthony Rosenzweig

    During aging, deterioration in cardiac structure and function leads to increased susceptibility to heart failure. The need for interventions to combat this age-related cardiac decline is becoming increasingly urgent as the elderly population continues to grow. Our understanding of cardiac aging, and aging in general, is limited. However, recent studies of age-related decline and its prevention through interventions like exercise have revealed novel pathological and cardioprotective pathways. In this review, we summarize recent findings concerning the molecular mechanisms of age-related heart failure and highlight exercise as a valuable experimental platform for the discovery of much-needed novel therapeutic targets in this chronic disease.

    更新日期:2020-02-14
  • Polyploidy in Cardiomyocytes
    Circ. Res. (IF 15.862) Pub Date : 2020-02-13
    Wouter Derks; Olaf Bergmann

    The hallmark of most cardiac diseases is the progressive loss of cardiomyocytes. In the perinatal period, cardiomyocytes still proliferate, and the heart shows the capacity to regenerate upon injury. In the adult heart, however, the actual rate of cardiomyocyte renewal is too low to efficiently counteract substantial cell loss caused by cardiac injury. In mammals, cardiac growth by cell number expansion changes to growth by cardiomyocyte enlargement soon after birth, coinciding with a period in which most cardiomyocytes increase their DNA content by multinucleation and nuclear polyploidization. Although cardiomyocyte hypertrophy is often associated with these processes, whether polyploidy is a prerequisite or a consequence of hypertrophic growth is unclear. Both the benefits of cardiomyocyte enlargement over proliferative growth of the heart and the physiological role of polyploidy in cardiomyocytes are enigmatic. Interestingly, hearts in animal species with substantial cardiac regenerative capacity dominantly comprise diploid cardiomyocytes, raising the hypothesis that cardiomyocyte polyploidy poses a barrier for cardiomyocyte proliferation and subsequent heart regeneration. On the contrary, there is also evidence for self-duplication of multinucleated myocytes, suggesting a more complex picture of polyploidy in heart regeneration. Polyploidy is not restricted to the heart but also occurs in other cell types in the body. In this review, we explore the biological relevance of polyploidy in different species and tissues to acquire insight into its specific role in cardiomyocytes. Furthermore, we speculate about the physiological role of polyploidy in cardiomyocytes and how this might relate to renewal and regeneration.

    更新日期:2020-02-14
  • Intestinal Flora Modulates Blood Pressure by Regulating the Synthesis of Intestinal-Derived Corticosterone in High Salt-Induced Hypertension
    Circ. Res. (IF 15.862) Pub Date : 2020-02-13
    Xuefang Yan; Jiajia Jin; Xinhuan Su; Xianlun Yin; Jing Gao; Xiaowei Wang; Shucui Zhang; Peili Bu; Mansen Wang; Yun Zhang; Zhe Wang; Qunye Zhang

    Rationale: High-salt diet (HSD) is one of the most important risk factors for hypertension. Intestinal flora has been reported to be associated with high salt-induced hypertension (hSIH). However, the detailed roles of intestinal flora in hSIH pathogenesis have not yet been fully elucidated.Objective: To reveal the roles and mechanisms of intestinal flora in hSIH development.Methods and Results: The above-mentioned issues were investigated using various techniques including 16S rRNA gene sequencing, untargeted metabolomics, selective bacterial culture and fecal microbiota transplantation (FMT). We found that HSD induced hypertension in Wistar rats. The fecal microbiota of healthy rats could dramatically lower blood pressure (BP) of hypertensive rats, while the fecal microbiota of hSIH rats had opposite effects. The composition, metabolism and interrelationship of intestinal flora in hSIH rats were considerably reshaped, including the increased corticosterone level and reduced Bacteroides and arachidonic acid (AA) levels, which tightly correlated with BP. The serum corticosterone level was also significantly increased in rats with hSIH. Furthermore, the above abnormalities were confirmed in patients with hypertension. The intestinal Bacteroides fragilis (B. fragilis) could inhibit the production of intestinal-derived corticosterone induced by HSD through its metabolite AA.Conclusions: hSIH could be transferred by FMT, indicating the pivotal roles of intestinal flora in hSIH development. HSD reduced the levels of B. fragilis and AA in the intestine, which increased intestinal-derived corticosterone production and corticosterone levels in serum and intestine, thereby promoting BP elevation. This study revealed a novel mechanism different from inflammation/immunity by which intestinal flora regulated BP, namely intestinal flora could modulate BP by affecting steroid hormone levels. These findings enriched the understanding of the function of intestinal flora and its effects on hypertension.

    更新日期:2020-02-13
  • A Novel "Cut And Paste" Method for In Situ Replacement of cMyBP-C Reveals a New Role for cMyBP-C in the Regulation of Contractile Oscillations
    Circ. Res. (IF 15.862) Pub Date : 2020-02-13
    Nathaniel Conrad Napierski; Kevin Granger; Paul R Langlais; Hannah R Moran; Joshua Strom; Katia D Youssef; Samantha P Harris

    Rationale: Cardiac myosin binding protein-C (cMyBP-C) is a critical regulator of heart contraction, but the mechanisms by which cMyBP-C affects actin and myosin are only partly understood. A primary obstacle is that cMyBP-C localization on thick filaments may be a key factor defining its interactions, but most in vitro studies cannot duplicate the unique spatial arrangement of cMyBP-C within the sarcomere.Objective: The goal of this study was to validate a novel hybrid genetic/protein engineering approach for rapid manipulation of cMyBP-C in sarcomeres in situ.Methods and Results: We designed a novel "cut and paste" approach for removal and replacement of cMyBP-C N'-terminal domains (C0-C7) in detergent-permeabilized cardiomyocytes from gene-edited "Spy-C" mice. Spy-C mice express a tobacco etch virus protease (TEVp) cleavage site and a "SpyTag" between cMyBP-C domains C7 and C8. A "cut" is achieved using TEVp which cleaves cMyBP-C to create a soluble N'-terminal gC0C7 fragment and an insoluble C'-terminal SpyTag (st)-C8-C10 fragment that remains associated with thick filaments. "Paste" of new recombinant (r)C0C7 domains is achieved by a covalent bond formed between SpyCatcher (-sc) (encoded at the C'-termini of recombinant proteins) and SpyTag. Results show that loss of gC0C7 reduced myofilament Ca2+ sensitivity and increased cross bridge cycling (ktr) at submaximal [Ca2+]. Acute loss of gC0C7 also induced auto-oscillatory contractions at submaximal [Ca2+]. Ligation of rC0C7-sc returned pCa50 and ktr to control values and abolished oscillations, but phosphorylated (p)-rC0C7-sc did not completely rescue these effects.Conclusions: We describe a robust new approach for acute removal and replacement of cMyBP-C in situ. The method revealed a novel role for cMyBP-C N'-terminal domains to damp sarcomere-driven contractile waves (so called "SPOC"). Because phosphorylated (p)-rC0C7-sc was less effective at damping contractile oscillations, results suggest that SPOC may contribute to enhanced contractility in response to inotropic stimuli.

    更新日期:2020-02-13
  • Dll4 Suppresses Transcytosis for Arterial Blood-Retinal Barrier Homeostasis
    Circ. Res. (IF 15.862) Pub Date : 2020-02-12
    Jee Myung Yang; Chan Soon Park; Soo Hyun Kim; Tae Wook Noh; Ju-Hee Kim; Seongyeol Park; Jingu Lee; Jang Ryul Park; Dohyun Yoo; Hyun Ho Jung; Hiroshi Takase; David T. Shima; Markus Schwaninger; Seungjoo Lee; Il-Kug Kim; Junyeop Lee; Yong-Sok Ji; Sangyong Jon; Wang-Yuhl Oh; Pilhan Kim; Akiyoshi Uemura; Young Seok Ju; Injune Kim

    Rationale: Central nervous system (CNS) has low vascular permeability by organizing tight junction (TJ) and limiting endothelial transcytosis. While TJ has long been considered to be responsible for barrier in CNS vessels, suppressed transcytosis in endothelial cells (ECs) is now emerging as a complementary mechanism. Whether transcytosis regulation is independent of TJ and its dysregulation dominantly causes diseases associated with edema remain elusive. Dll4 signaling is important for various vascular contexts but its role in the maintenance of CNS vascular barrier remains unknown.Objective: To find a TJ-independent regulatory mechanism selective for transcytosis and identify its dysregulation as a cause of pathological leakage.Methods and Results: We studied transcytosis in the adult mouse retina with low vascular permeability and employed a hypertension-induced retinal edema model for its pathological implication. Both antibody-based and genetic inactivation of Dll4 or Notch1 induce hyperpermeability by increasing transcytosis without junctional destabilization in arterial ECs, leading to non-hemorrhagic leakage predominantly in the superficial retinal layer. Endothelial Sox17 deletion represses Dll4 in retinal arteries, phenocopying Dll4 blocking-driven vascular leakage. Angiotensin II-induced hypertension represses arterial Sox17 and Dll4, followed by transcytosis-driven retinal edema, which is rescued by a gain of Notch activity. Transcriptomic profiling of retinal ECs suggests that Dll4 blocking activates SREBP1-mediated lipogenic transcription and enriches gene sets favorable for caveolae formation. Profiling also predicts the activation of VEGF signaling by Dll4 blockade. Inhibition of SREBP1 or VEGF-VEGFR2 signaling attenuates both Dll4 blockade-driven and hypertension-induced retinal leakage.Conclusions: In the retina, Sox17-Dll4-SREBP1 signaling axis controls transcytosis independently of TJ in superficial arteries among heterogeneous regulations for the whole vessels. Uncontrolled transcytosis via dysregulated Dll4 underlies pathological leakage in hypertensive retina and could be a therapeutic target for treating hypertension-associated retinal edema.

    更新日期:2020-02-12
  • BMAL1-Downregulation Aggravates Porphyromonas Gingivalis-Induced Atherosclerosis by Encouraging Oxidative Stress
    Circ. Res. (IF 15.862) Pub Date : 2020-02-11
    Mengru Xie; Qingming Tang; Jiaming Nie; Chao Zhang; Xin Zhou; Shaoling Yu; Jiwei Sun; Xiang Cheng; Nianguo Dong; Yu Hu; Lili Chen

    Rationale: Atherosclerotic cardiovascular diseases (ACVDs) are the leading cause of mortality worldwide. ACVDs are considered as chronic inflammation processes. In addition to risk factors associated with the cardiovascular system itself, pathogenic bacteria such as the periodontitis-associated Porphyromonas gingivalis (P. gingivalis) are also closely correlated with the development of atherosclerosis, but the underlying mechanisms are still elusive.Objective: To elucidate the mechanisms of P. gingivalis-accelerated atherosclerosis and explore novel therapeutic strategies of ACVDs.Methods and Results:Bmal1-/- mice, ApoE-/- mice, Bmal1-/-ApoE-/- mice, conditional endothelial cell Bmal1 knockout mice (Bmal1fl/fl; Tek-Cre mice), and the corresponding jet-legged mouse model were used. P. gingivalis accelerates atherosclerosis progression by triggering arterial oxidative stress and inflammatory responses in ApoE-/- mice, accompanied by the perturbed circadian clock. Circadian clock disruption boosts P. gingivalis-induced atherosclerosis progression. The mechanistic dissection shows that P. gingivalis infection activates the TLRs-NF-κB signaling axis, which subsequently recruits DNMT-1 to methylate the BMAL1 promoter and thus suppresses BMAL1 transcription. The downregulation of BMAL1 releases CLOCK, which phosphorylates p65 and further enhances NF-κB signaling, elevating oxidative stress and inflammatory response in human aortic endothelial cells. Besides, the mouse model exhibits that joint administration of metronidazole and melatonin serves as an effective strategy for treating ACVDs.Conclusions:P. gingivalis accelerates atherosclerosis via the NF-κB-BMAL1-NF-κB signaling loop. Melatonin and metronidazole are promising auxiliary medications toward ACVDs.

    更新日期:2020-02-11
  • Exome-Based Case-Control Analysis Highlights the Pathogenic Role of Ciliary Genes in Transposition of the Great Arteries
    Circ. Res. (IF 15.862) Pub Date : 2020-02-11
    Xuanyu Liu; Wen Chen; Wenke Li; James R. Priest; Yuanyuan Fu; Kun-Jing Pang; Baihui Ma; Bianmei Han; Xuewen liu; Shengshou Hu; Zhou Zhou

    Rationale: Transposition of the great arteries (TGA) is one of the most severe types of congenital heart diseases (CHD). Understanding the clinical characteristics and pathogenesis of TGA is therefore urgently needed for patient management of this severe disease. However, the clinical characteristics and genetic etiology underlying TGA remain largely unexplored.Objective: We sought to systematically examine the clinical characteristics and genetic etiology for isolated nonsyndromic TGA.Methods and Results: We recruited 249 TGA patients (66 family trios) and performed whole-exome sequencing. The incidence of patent ductus arteriosus in dextro-TGA (52.7%) and dextrocardia/mesocardia in congenitally corrected TGA (32.8%) were significantly higher than that in other subtypes. A high prevalence of bicuspid pulmonic valve (9.6%) was observed in TGA patients. Similar results were observed in a replication group of TGA (n=132). Through a series of bioinformatics filtering steps, we obtained 82 candidate genes harboring potentially damaging de novo, loss of function, compound heterozygous or X-linked recessive variants. Established CHD-causing genes, such as FOXH1, were found among the list of candidate genes. A total of 19 ciliary genes harboring rare potentially damaging variants were also found; for example, DYNC2LI1 with a de novo putatively damaging variant. The enrichment of ciliary genes supports the roles of cilia in the pathogenesis of TGA. In total, 33% of the TGA probands had more than one candidate gene hit by putatively deleterious variants, suggesting that a portion of the TGA cases were probably affected by oligogenic or polygenic inheritance.Conclusions: The findings of clinical characteristic analyses have important implications for TGA patient stratification. The results of genetic analyses highlight the pathogenic role of ciliary genes and a complex genetic architecture underlying TGA.

    更新日期:2020-02-11
  • B-Cell Specific CXCR4 Protects Against Atherosclerosis Development and Increases Plasma IgM Levels
    Circ. Res. (IF 15.862) Pub Date : 2020-02-05
    Yvonne Döring; Yvonne Jansen; Ismail Cimen; Maria Aslani; Selin Gencer; Linsey JF Peters; Johan Duchene; Christian Weber; Emiel van van der Vorst

    N/A

    更新日期:2020-02-06
  • Non-Invasive In Vivo Assessment of Cardiac Metabolism in the Healthy and Diabetic Human Heart Using Hyperpolarized 13C MRI
    Circ. Res. (IF 15.862) Pub Date : 2020-02-05
    Oliver J Rider; Andrew Apps; Jack J Miller; Justin YC Lau; Andrew JM Lewis; Mark A Peterzan; Michael S Dodd; Angus Z Lau; Claire Trumper; Ferdia Gallagher; James T Grist; Kevin Brindle; Stefan Neubauer; Damian J Tyler

    Rationale: The recent development of hyperpolarized 13C Magnetic Resonance Spectroscopy (MRS) has made it possible to measure cellular metabolism in vivo, in real time.Objective: By comparing participants with and without type 2 diabetes (T2DM), we report the first case-control study to use this technique to record changes in cardiac metabolism in the healthy and diseased human heart.Methods and Results: Thirteen people with type 2 diabetes (HbA1c 6.9{plus minus}1.0%) and 12 age-matched healthy controls underwent assessment of cardiac systolic and diastolic function, myocardial energetics (31P-MRS) and lipid content (1H-MRS) in the fasted state. In a subset (5 T2DM, 5 control), hyperpolarized [1-13C]pyruvate MR spectra were also acquired and in five of these participants (3 T2DM, 2 controls), this was successfully repeated 45 minutes after a 75g oral glucose challenge. Downstream metabolism of [1-13C]pyruvate via pyruvate dehydrogenase (PDH, [13C]bicarbonate), lactate dehydrogenase ([1-13C]lactate) and alanine transaminase ([1-13C]alanine) was assessed. Metabolic flux through cardiac PDH was significantly reduced in the people with type 2 diabetes (Fasted:0.0084{plus minus}0.0067[Control] vs. 0.0016{plus minus}0.0014[T2DM], Fed:0.0184{plus minus}0.0109 vs. 0.0053{plus minus}0.0041, p=.013). In addition, a significant increase in metabolic flux through PDH was observed after the oral glucose challenge (p<.001). As is characteristic of diabetes, impaired myocardial energetics, myocardial lipid content and diastolic function were also demonstrated in the wider study cohort.Conclusions: This work represents the first demonstration of the ability of hyperpolarized 13C MRS to non-invasively assess physiological and pathological changes in cardiac metabolism in the human heart. In doing so, we highlight the potential of the technique to detect and quantify metabolic alterations in the setting of cardiovascular disease.

    更新日期:2020-02-06
  • Identification of a Primary Renal AT2 Receptor Defect in Spontaneously Hypertensive Rats
    Circ. Res. (IF 15.862) Pub Date : 2020-01-30
    Brandon A Kemp; Nancy L Howell; John J Gildea; Susanna R Keller; Robert M Carey

    Rationale: Previous studies identified a defect in angiotensin III (Ang III)-elicited AT2 receptor (AT2R)-mediated natriuresis in renal proximal tubule cells (RPTCs) of spontaneously hypertensive rats (SHR).Objective: This study aimed to delineate in pre-hypertensive SHR kidneys the receptor and/or post-receptor defect causing impaired AT2R signaling and renal sodium (Na+) retention by utilizing the selective AT2R agonist Compound 21 (C-21).Methods and Results: Female 4-week-old Wistar-Kyoto (WKY) and SHR rats were studied after 24h systemic AT1 receptor (AT1R) blockade. Left kidneys received 30 min renal interstitial (RI) infusions of vehicle followed by C-21 (20, 40, and 60 ng/kg/min, each dose 30 min). Right kidneys received vehicle infusions. In WKY, C-21 dose-dependently increased urine Na+ excretion (UNaV) from 0.023{plus minus}0.01 to 0.064{plus minus}0.02, 0.087{plus minus}0.01, and 0.089{plus minus}0.01 µmol/min (P=0.008, P<0.0001, and P<0.0001, respectively) and RI fluid levels of AT2R downstream signaling molecule cGMP from 0.91{plus minus}0.3 to 3.1{plus minus}1.0, 5.9{plus minus}1.2, and 5.3{plus minus}0.5 fmol/mL (P=NS, P<0.0001, and P<0.0001, respectively). In contrast, C-21 did not increase UNaV or RI cGMP in SHR. Mean arterial pressure was slightly higher in SHR, but within the normotensive range and unaffected by C-21. In WKY, but not SHR, C-21 induced AT2R translocation to apical plasma membranes of RPTCs, internalization/inactivation of NHE-3 and Na+/K+ATPase and phosphorylation of AT2R-cGMP downstream signaling molecules Src kinase, extracellular signal-related kinase (ERK), and vasodilator-stimulated phosphoprotein (VASP). To test whether cGMP could bypass the natriuretic defect in SHR, we infused 8-Br-cGMP. This restored natriuresis, Na+ transporter internalization/inactivation, and Src and VASP phosphorylation, but not apical plasma membrane AT2R recruitment. In contrast, 8-Br-cAMP administration had no effect on natriuresis or AT2R recruitment in SHR.Conclusions: The results demonstrate a primary RPTC AT2R natriuretic defect in SHR that may contribute to the development of hypertension. Since the defect is abrogated by exogenous intrarenal cGMP, the renal cGMP pathway may represent a viable target for the treatment of hypertension.

    更新日期:2020-01-31
  • In This Issue
    Circ. Res. (IF 15.862) Pub Date : 2020-01-30
    Ruth Williams

    Stem and progenitor cells for treating injured hearts are thought to exert their effects via paracrine pathways such as the release of tiny vesicles called exosomes. Indeed, exosomes have been shown to work similarly to their parent cells. Whatever the mechanism, cell therapy trials have produced modest benefits at best. One factor limiting success, suggest Yue and colleagues, is the systemic inflammation experienced by many patients after myocardial infarction. Indeed, endothelial progenitor cells (EPCs) from patients with systemic inflammation have lower-than-usual survival and angiogenic capacity. And EPC-derived exosomes from a mouse model of systemic inflammation are similarly deficient at promoting angiogenesis and cell survival in vitro. The team now shows that these exosomes from the model mice also have reduced reparative function compared with wild-type exosomes when used to treat the hearts of live mice. An increased level of integrin-linked kinase (ILK)—an activator of the proinflammatory factor NFκB—was deemed the root of the problem as knock-down of the kinase restored the exosomes’ reparative capacity. Together, the results suggest that manipulating ILK levels could improve the effectiveness of exosomes as a potential cardiac therapy. Atrial fibrillation (AF) is the most common form of heart arrhythmia, with somewhere between 3 and 6 million sufferers in the US alone. The condition can be either idiopathic or inherited, and hundreds of genetic loci have been linked to AF via genome-wide association studies (GWASs). These loci explain only a small percentage of the inherited cases, however, suggesting there are many more AF-related genes yet to be discovered. To identify these elusive loci, Wang and colleagues have now integrated data from previously performed transcriptome- and epigenome-wide association studies (TWAS and EWAS)—each consisting of more than 150 AF patients and more than 2000 controls—with existing GWAS data from tens of thousands of AF and control participants. By analyzing data from these TWAS, EWAS, and GWAS studies en masse, the team was able to identify 1931 genes associated with AF compared with just 206 identified via the GWAS alone. Many of the genes are involved in the development and regulation of the heart and muscles, say the authors. The additional gene hunting power afforded by coanalyzing multiple-omics data is not only a helpful approach for AF but for numerous other diseases of complex etiology. Alterations to the gut microbiome have been suggested to influence the risk of developing certain chronic diseases, including cardiovascular disease and cancer. And such alterations can result from antibiotic use. Indeed, preliminary evidence suggests long-term antibiotic use may be linked to increased mortality in adult women. Heianza and colleagues now investigate this link in more detail, performing a large-scale population study of antibiotic use in middle-aged and older women with a follow-up period of 10 years. The team’s analysis of 37 516 women, who were in middle age (40–59 years) or late age (over 60) at the start of the study, revealed that long-durations of antibiotic use were associated with increased risk of all-cause mortality and of cardiovascular disease-related mortality in late adulthood even after adjusting for risk factors such as age, lifestyle, diet, and obesity. While no such association was apparent in middle-aged women, the risk for older women was more pronounced if they had also used antibiotics during middle life, suggesting the risk maybe cumulative. While antibiotics unquestionably save lives and the link is not necessarily causative, the results indicate a potential risk may exist that could be factored into prescription decisions.

    更新日期:2020-01-31
  • Meet the First Author
    Circ. Res. (IF 15.862) Pub Date : 2020-01-30

    Dr Dan Tyrrell is a postdoctoral fellow in Dr Daniel Goldstein’s laboratory at the University of Michigan. He completed his PhD in Dr Anthony Molina’s laboratory in Integrative Physiology and Pharmacology at Wake Forest School of Medicine. Dan’s recent work demonstrates a positive feedback loop of increased IL-6 and mitochondrial dysfunction within the aging aorta that accelerates atherogenesis. His long-term goal is to determine how mitochondria and inflammation interact in multiple vascular beds with aging, and how these changes enhance disease. Dan enjoys running and biking when he isn’t spending time with his family (ie, chasing after his two young sons). He can be found on Twitter @dantyrr. Dr Yujia Yue earned her BS in Medicine from Fudan University in China. She became interested in life sciences and basic biomedical research while earning her MD. She came to the US in 2014 and completed her PhD in May 2019 (mentor, Dr Raj Kishore) at the Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, focusing on stem cell-derived exosome in cardiac regeneration. After earning her PhD, Yujia joined Merck as an Associate Scientist. She is interested in furthering her scientific pursuit of translational medicine and drug discovery and plans to continue her scientific career in industry. Dr Zhifen Chen is a postdoctoral fellow in Dr Chad Cowan’s group at the Harvard Stem Cell Institute, where her research focuses on functional genomics of polygenic traits, including insulin resistance and glucose levels. She earned her PhD from Technical University of Munich (TUM) in 2016 and her MS from Tsinghua University, Beijing, in 2012. She was mentored by Dr Karl-Ludwig Laugwitz, focussing on cardiac disease modelling using patient-induced pluripotent stem cell (iPSC)-derived cardiomyocytes, including a type of long QT syndrome and a case of familial dilated cardiomyopathy. The goal of her research is to identify unknown genes contributing to adipose insulin resistance and test their therapeutic potentials for obesity or type 2 diabetes and their related cardiometabolic comorbidities. Outside of the lab, she enjoys dancing, biking, and discussing life experiences and diverse fields of science. She plans to establish her own lab in the near future. Julie Heffler is a doctoral candidate at the University of Pennsylvania in the lab of Dr Ben Prosser. She began her career as an undergraduate at the University of Houston, where she earned her BS in Biochemistry. During her time at UH, she worked in the lab of Dr Kevin Morano at UT Health researching chaperones and protein misfolding. Currently, her research at UPenn has focused on the attachment of the cytoskeleton to the nucleus in adult cardiomyocytes and how these cells sense mechanical signals, continuing her long-held interest in cell sensing and signal transduction. She can be found on Twitter @julieheffler. Dr Yoriko Heianza is a postdoctoral research fellow in the Department of Epidemiology at Tulane University. She earned her PhD in Medicine from the University of Tsukuba, Japan. She previously earned her BS from the Doshisha Women’s College of Liberal Arts, Kyoto, Japan, where she gained a broad knowledge of nutrition. She has been exploring genetic, metabolomic, diet/lifestyle factors in the development of obesity and cardiovascular disease in Dr Lu Qi’s Lab at Tulane University, with the support of an AHA Postdoctoral Fellowship. She has also received two awards for her research from the AHA.

    更新日期:2020-01-31
  • Age-Associated Mitochondrial Dysfunction Accelerates Atherogenesis
    Circ. Res. (IF 15.862) Pub Date : 2019-12-09
    Daniel J. Tyrrell; Muriel G. Blin; Jianrui Song; Sherri C. Wood; Min Zhang; Daniel A. Beard; Daniel R. Goldstein

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    更新日期:2020-01-31
  • Interleukin-10 Deficiency Alters Endothelial Progenitor Cell–Derived Exosome Reparative Effect on Myocardial Repair via Integrin-Linked Kinase Enrichment
    Circ. Res. (IF 15.862) Pub Date : 2019-12-09
    Yujia Yue; Chunlin Wang; Cindy Benedict; Grace Huang; May Truongcao; Rajika Roy; Maria Cimini; Venkata Naga Srikanth Garikipati; Zhongjian Cheng; Walter J. Koch; Raj Kishore

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    更新日期:2020-01-31
  • Functional Screening of Candidate Causal Genes for Insulin Resistance in Human Preadipocytes and Adipocytes
    Circ. Res. (IF 15.862) Pub Date : 2019-11-19
    Zhifen Chen; Haojie Yu; Xu Shi; Curtis R. Warren; Luca A. Lotta; Max Friesen; Torsten B. Meissner; Claudia Langenberg; Martin Wabitsch; Nick Wareham; Mark D. Benson; Rob E. Gerszten; Chad A. Cowan

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    更新日期:2020-01-31
  • A Balance Between Intermediate Filaments and Microtubules Maintains Nuclear Architecture in the Cardiomyocyte
    Circ. Res. (IF 15.862) Pub Date : 2019-12-11
    Julie Heffler; Parisha P. Shah; Patrick Robison; Sai Phyo; Kimberly Veliz; Keita Uchida; Alexey Bogush; Joshua Rhoades; Rajan Jain; Benjamin L. Prosser

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    更新日期:2020-01-31
  • Integrative Omics Approach to Identifying Genes Associated With Atrial Fibrillation
    Circ. Res. (IF 15.862) Pub Date : 2019-12-05
    Biqi Wang; Kathryn L. Lunetta; Josée Dupuis; Steven A. Lubitz; Ludovic Trinquart; Lixia Yao; Patrick T. Ellinor; Emelia J. Benjamin; Honghuang Lin

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    更新日期:2020-01-31
  • Duration and Life-Stage of Antibiotic Use and Risks of All-Cause and Cause-Specific Mortality
    Circ. Res. (IF 15.862) Pub Date : 2019-12-17
    Yoriko Heianza; Wenjie Ma; Xiang Li; Yin Cao; Andrew T. Chan; Eric B. Rimm; Frank B. Hu; Kathryn M. Rexrode; JoAnn E. Manson; Lu Qi

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    更新日期:2020-01-31
  • The Role of the Epicardium During Heart Development and Repair
    Circ. Res. (IF 15.862) Pub Date : 2020-01-30
    Pearl Quijada; Michael A. Trembley; Eric M. Small

    The heart is lined by a single layer of mesothelial cells called the epicardium that provides important cellular contributions for embryonic heart formation. The epicardium harbors a population of progenitor cells that undergo epithelial-to-mesenchymal transition displaying characteristic conversion of planar epithelial cells into multipolar and invasive mesenchymal cells before differentiating into nonmyocyte cardiac lineages, such as vascular smooth muscle cells, pericytes, and fibroblasts. The epicardium is also a source of paracrine cues that are essential for fetal cardiac growth, coronary vessel patterning, and regenerative heart repair. Although the epicardium becomes dormant after birth, cardiac injury reactivates developmental gene programs that stimulate epithelial-to-mesenchymal transition; however, it is not clear how the epicardium contributes to disease progression or repair in the adult. In this review, we will summarize the molecular mechanisms that control epicardium-derived progenitor cell migration, and the functional contributions of the epicardium to heart formation and cardiomyopathy. Future perspectives will be presented to highlight emerging therapeutic strategies aimed at harnessing the regenerative potential of the fetal epicardium for cardiac repair.

    更新日期:2020-01-31
  • The Control of Diastolic Calcium in the Heart
    Circ. Res. (IF 15.862) Pub Date : 2020-01-30
    David A. Eisner; Jessica L. Caldwell; Andrew W. Trafford; David C. Hutchings

    Normal cardiac function requires that intracellular Ca2+ concentration be reduced to low levels in diastole so that the ventricle can relax and refill with blood. Heart failure is often associated with impaired cardiac relaxation. Little, however, is known about how diastolic intracellular Ca2+ concentration is regulated. This article first discusses the reasons for this ignorance before reviewing the basic mechanisms that control diastolic intracellular Ca2+ concentration. It then considers how the control of systolic and diastolic intracellular Ca2+ concentration is intimately connected. Finally, it discusses the changes that occur in heart failure and how these may result in heart failure with preserved versus reduced ejection fraction.

    更新日期:2020-01-31
  • Life-Course Cumulative Burden of Body Mass Index and Blood Pressure on Progression of Left Ventricular Mass and Geometry in Midlife: The Bogalusa Heart Study
    Circ. Res. (IF 15.862) Pub Date : 2020-01-29
    Yinkun Yan; Shengxu Li; Yajun Guo; Camilo Fernandez; Lydia A Bazzano; Jiang He; Jie Mi; Wei Chen

    Rationale: Data are limited regarding the influence of life-course cumulative burden of increased body mass index (BMI) and elevated blood pressure on the progression of left ventricular (LV) geometric remodeling in midlife.Objective: To investigate the dynamic changes in LV mass and LV geometry over 6.4 years during midlife and to examine whether the adverse progression of LV geometric remodeling is influenced by the cumulative burden of BMI and blood pressure from childhood to adulthood.Methods and Results: The study consisted of 877 adults (604 whites and 273 blacks; 355 males; mean age=41.4 years at follow-up) who had 5-15 examinations of BMI and blood pressure from childhood and 2 examinations of LV dimensions at baseline and follow-up 6.4 years apart during adulthood. The area under the curve (AUC) was calculated as a measure of long-term burden (total AUC) and trends (incremental AUC) of BMI and systolic blood pressure (SBP). After adjusting for age, race, sex, smoking, alcohol drinking and baseline LV mass index, the annual increase rate of LV mass index was associated with all BMI measures (β=0.16-0.36, P<0.05 for all), adult SBP (β=0.07, P=0.04), and total AUC of SBP (β=0.09, P=0.01), but not with childhood and incremental AUC values of SBP. All BMI and SBP measures (except childhood SBP) were significantly associated with increased risk of incident LV hypertrophy, with odds ratios (ORs) of BMI (OR=1.85-2.74, P<0.05 for all) being significantly greater than those of SBP (OR=1.09-1.34, P<0.05 for all except childhood SBP). In addition, all BMI measures were significantly and positively associated with incident eccentric and concentric LV hypertrophy.Conclusions: Life-course cumulative burden of BMI and blood pressure is associated with the development of LVH in midlife, with BMI showing stronger associations than blood pressure.

    更新日期:2020-01-29
  • Mildly Abnormal Lipid Levels, but Not High Lipid Variability, Are Associated with Increased Risk of Myocardial Infarction and Stroke in 'Statin-Naive' Young Population: A Nationwide Cohort Study
    Circ. Res. (IF 15.862) Pub Date : 2020-01-24
    Jun-Bean Park; Dahye Kim; Heesun Lee; In-Chang Hwang; Yeonyee Elizabeth Yoon; Hyo Eun PARK; Su-Yeon Choi; Yong-Jin Kim; Goo-Yeong Cho; Kyung-Do Han; Hyung-Kwan Kim

    Rationale: In young adults, the role of mildly abnormal lipid levels and lipid variability in the risk of atherosclerotic cardiovascular diseases (ASCVDs) remains uncertain.Objective: To investigate the association of these abnormalities in lipid profiles with the risk of myocardial infarction (MI) and stroke in young population.Methods and Results: From the Korean National Health Insurance Service, a nationwide population-based cohort of 1,934,324 'statin-naive' adults aged 20-39 years, with {greater than or equal to}3 lipid profile measurements and without a history of MI and stroke, were followed-up until the date of MI or stroke, or December 31, 2017. The primary measure of lipid variability was variability independent of the mean. Higher baseline total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), and triglycerides and lower high-density lipoprotein-cholesterol (HDL-C) levels were significantly associated with increased MI risk; respective adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) comparing the highest vs. lowest quartiles were 1.35 (1.20-1.53) for TC, 1.41 (1.25-1.60) for LDL-C, 1.28 (1.11-1.47) for triglycerides, and 0.82 (0.72-0.94) for HDL-C. Adjusted analyses for deciles of lipid profiles showed that MI risk was significantly elevated among participants with TC {greater than or equal to}223.4mg/dL, LDL-C {greater than or equal to}139.5mg/dL, HDL-C {less than or equal to}41.8mg/dL, and triglycerides {greater than or equal to}200.1mg/dL. The associations between lipid levels and stroke risk were less prominent. Multivariable-adjusted restricted cubic spline analysis demonstrated that the increase in MI risk was not exclusively driven by extreme values of lipid profiles. Similar results were obtained on sensitivity analyses of baseline lipid levels. However, associations between lipid variability and the risk of MI and stroke varied depending on the measure of lipid variability used.Conclusions: Mildly abnormal baseline lipid levels were associated with an increased future risk of ASCVD events, particularly MI, whereas measures of lipid variability were not. Therefore, in young adults, achieving optimal lipid levels could be valuable in the prevention of ASCVD.

    更新日期:2020-01-26
  • Brain Damage with Heart Failure: Cardiac Biomarker Alterations and Gray Matter Decline
    Circ. Res. (IF 15.862) Pub Date : 2020-01-23
    Karsten Mueller; Friederike Thiel; Frank Beutner; Andrej Teren; Stefan Frisch; Tommaso Ballarini; Harald E Möller; Kristin Ihle; Joachim Thiery; Gerhard C Schuler; Arno Villringer; Matthias L Schroeter

    Rationale: Heart failure (HF) following heart damage leads to a decreased blood flow due to a reduced pump efficiency of the heart muscle. A consequence can be insufficient oxygen supply to the organism including the brain. While HF clearly shows neurological symptoms, such as fatigue, nausea and dizziness, the implications for brain structure are not well understood. Few studies show regional gray matter decrease related to HF, however, the underlying mechanisms leading to the observed brain changes remain unclear.Objective: To study the relationship between impaired heart function, hampered blood circulation and structural brain change in a case-control study.Methods and Results: Within a group of 80 patients of the Leipzig Heart Center, we investigated a potential correlation between HF biomarkers and the brain's gray matter density (GMD) obtained by magnetic resonance imaging. We observed a significant positive correlation between cardiac ejection fraction and GMD across the whole frontal and parietal medial cortex reflecting the consequence of HF onto the brain's gray matter. Moreover, we also obtained a relationship between GMD and the N-terminal prohormone of brain natriuretic peptide (NT-proBNP) − a biomarker that is used for screening, diagnosis and prognosis of HF. Here we found a significant negative correlation between NT-proBNP and GMD in the medial and posterior cingulate cortex but also in precuneus and hippocampus, which are key regions implicated in structural brain changes in dementia.Conclusions: We obtained significant correlations between brain structure and markers of heart failure including EF and NT-proBNP. A diminished GMD was found with decreased EF and increased NT-proBNP in wide brain regions including the whole frontomedian cortex as well as hippocampus and precuneus. Our observations might reflect structural brain damage in areas that are related to cognition, however, whether these structural changes facilitate the development of cognitive alterations has to be proven by further longitudinal studies.

    更新日期:2020-01-23
  • In This Issue
    Circ. Res. (IF 15.862) Pub Date : 2020-01-16
    Ruth Williams

    Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, life-threatening form of pulmonary hypertension characterized by persistent blood clots in the lung arteries that ultimately result in the formation of fibrotic lesions containing irregular vasculature. The mechanisms underlying CTEPH are largely unknown, but because the cytokine TGFβ1 regulates fibrosis and angiogenesis, and because mutations affecting TGFβ1 signaling have been implicated in another form of pulmonary hypertension, Bochenek and colleagues hypothesized this factor’s involvement. Sure enough, they found that, in CTEPH patient tissue, components of the TGFβ1 pathway were upregulated, including TGFβ1 itself and endothelin-1—a vasoconstrictor and promoter of fibrosis. The team also showed that mice engineered to lack TGFβ1 in platelet cells had faster resolution of experimental thrombosis than did control animals. Furthermore, inhibition of endothelin-1 activity prevented human and mouse endothelial cells converting to a fibrotic phenotype. The results suggest the TGFβ1-to-endothelin-1 pathway plays a pathological role in CTEPH and lends supporting evidence that the clinical use of endothelin-1 receptor blockers—prescribed to some patients with CTEPH—is a worthwhile therapy. Cardiac hypertrophy, in which the heart and its component cells become enlarged, can be a normal physiological process to cope with increased demand—for example, in pregnancy or elite athletes—but can also be pathological—caused by high blood pressure and other cardiovascular conditions. Pathological hypertrophy is associated with a metabolic switch in the heart from primarily fatty acid-based to glucose-based. And, boosting fatty acid oxidation (FAO) can protect against hypertrophy in cultured cardiomyocytes and animals. The mechanism underlying this protection is unknown, however. Now, Ritterhoff and colleagues show that in addition to increased glucose consumption, hypertrophic rat cardiomyocytes ramp up their levels of aspartate—a molecule involved in cell growth via synthesis of nucleic acids, RNAs, and proteins. And, boosting FAO (by genetic manipulation) prevents both the aspartate rise and hypertrophy in the cells as well as in live mice. Adding aspartate to such FAO-boosted cells could reinstate the hypertrophic phenotype. The discovery of this relationship between glucose metabolism, aspartate, and FAO may inform the design of new therapies aimed at manipulating heart cell metabolism to manage hypertrophy, say the authors. Affecting ≈30 million individuals worldwide, atrial fibrillation (AF) is a common cardiac arrhythmia associated with an increased risk of heart failure, stroke, dementia, and death. While the condition can be idiopathic, there is also evidence of inheritance. Indeed, a quarter of patients have a parent, sibling, or child with the condition. Genome-wide association studies have identified numerous common genetic variants linked to AF, and the more of these variants a person carries, the greater the risk—referred to as their polygenic risk score (PRS). Studies of families with AF have also revealed rarer monogenic variants, such as loss-of-function (LOF) mutations in the sarcomeric gene titin (TTN). Now, Choi and colleagues look at these common polygenic and rare monogenic variants together to examine their relative contributions. Studying the genomes of 1546 AF patients and more than 41 000 controls, the team discovered a significant association between AF and rare LOF variants at TTN. Indeed, 14% of individuals with such variants had AF. However, the team also showed that while TTN variants were highly penetrant, PRS scores accounted for considerably more of the variance in AF susceptibility. Thus, the study indicates that, generally speaking, a person’s PRS is a better indicator of overall AF risk.

    更新日期:2020-01-17
  • Meet the First Authors
    Circ. Res. (IF 15.862) Pub Date : 2020-01-16

    Dr Magdalena Ludmila Bochenek is a senior postdoctoral research associate with Dr Katrin Schäfer at the Department of Cardiology I and the Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz (Germany). She earned her MS in Medical Biochemistry from the University of Reims (France) and completed her PhD in 2009 in the laboratory of Dr Catherine Nobes at the University of Bristol (United Kingdom). It was at this time that she became interested in endothelial cell biology and angiogenesis. After earning her PhD, she joined Dr Ralf Adams in the Department of Tissue Morphogenesis at the Max-Planck-Institute in Münster, Germany, where she further worked on the role of novel candidate proteins in angiogenesis. In 2013, she joined Katrin Schäfer in Mainz and was awarded a CTH Virchow Fellowship to foster young academics in 2014. Her research focuses on endothelial-related processes leading to thrombus nonresolution, with strong bench-to-bed translational aspects. Outside the lab, she enjoys spending time with her family. Dr Julia Ritterhoff is an Acting Instructor at the Mitochondria and Metabolism Center at the University of Washington (UW). After completing her PhD at the University of Heidelberg in Germany, Julia joined Dr Rong Tian’s laboratory in 2015. She is interested in understanding which factors contribute to cardiac disease progression, and especially how metabolic rewiring leads to different forms of cardiac growth. Intrigued by many metabolic questions, Julia plays a large role in project management and mentorship of junior lab members. When she is not chasing different metabolites in the lab, she chases after her kids who keep her grounded and make sure she doesn’t spend too much time at work. Julia thinks writing papers and grants is more fun than running experiments, and she is eager to run her own lab. She can be found on Twitter @JuliaRitterhoff. Dr Seung Hoan Choi is a postdoctoral associate in the laboratory of Drs Patrick Ellinor and Steven Lubitz in the Cardiovascular Disease Initiative at the Broad Institute of MIT and Harvard. He earned his PhD from the Department of Biostatistics at Boston University with research focused on statistical genetics. His long-term interests are developing and applying novel statistical methods to elucidate the genetic basis of complex diseases. To achieve this goal, he has been developing his analytic capabilities in genetics, statistics, and large-scale data processing. During his postdoctoral training, he has used this foundation to elucidate the genetic basis of a common and complex human disease, atrial fibrillation. When he is not in the lab, he enjoys spending time with his family and two young children. Sean Jurgens is a medical student at the University of Amsterdam and a research intern at the Broad Institute of MIT and Harvard. Under the supervision of Drs Patrick Ellinor and Steven Lubitz, his research has focused on the genetic underpinnings of cardiac electrophysiology and arrhythmia in the general population. Sean earned his BS at the University of Amsterdam in 2018 and is currently working towards both an MD and an MS. Sean aspires to improve societal health by becoming a physician-scientist who can translate fundamental scientific findings to clinical utility. Outside of the lab, and the clinic, he enjoys fitness, karate, and attending musical performances ranging from classical to house music. Dr Yunhui Du earned her MS in Molecular Biotechnology (2005) at the University of Sydney and PhD in Physiology (2012) at the Capital Medical University, China. She completed her postdoctoral training in Dr Xinliang Ma’s lab at Thomas Jefferson University’s Department of Emergency Medicine in 2015. Currently, she is an Assistant Investigator (Assistant Professor equivalent) at the Beijing Institute of Heart, Lung and Vascular Diseases, Beijing Anzhen Hospital. Her research focuses on uncovering novel signalling transduction pathways leading to increased cardiovascular disease in obstructive sleep apnea and diabetes. She hopes to identify novel strategies effective to reduce obstructive sleep apnea/diabetes-related cardiovascular complications. Outside of work, Dr Du enjoys spending time with family and likes to travel around the world. Dr Nenja Krüger earned her BS in Molecular Cell Biology in Heidelberg and her MS in Molecular Medicine in Göttingen. During her Master’s studies, she became interested in cardiovascular biology, especially related to metabolism. For this reason, she decided to pursue her PhD in an international cardiovascular graduating program (IRTG 1902) between the University of Düsseldorf (Mentor, Ulrich Rüther) and the University of Virginia in Charlottesville (Mentor, Brant Isakson). During this time, she focused on obesity-associated diseases and vascular biology. Specifically, she analyzed the importance of endothelial cells in the complexity of obesity-induced hypertension and diabetes. The international PhD has provided multiple collaborations and colleagues. In her free time, she loves to cook and tries as many different international recipes as she can. Dr Simon Tual-Chalot earned his PhD in Cardiovascular Physiology in 2011 from the University of Angers, France. Interested in pursuing a research career in cardiovascular biology, he earned a Marie Curie Intra-European Fellowship in 2013 to work with Dr Helen Arthur at Newcastle University on the cardioprotective role of endoglin. In 2015, he became a joint investigator on a British Heart Foundation grant and was awarded a “Young Investigator Award” from Cure HHT to continue investigations on how endothelial endoglin regulates cardiovascular integrity. Currently, Dr Tual-Chalot is deputy group leader in Dr Konstantinos Stellos’s lab (www.stelloslab.com) at Newcastle University working on endothelial epitranscriptomics and he is eager to become a driving force in tomorrow’s cardiovascular research. Outside research, he is a keen ultra-runner, has a very caring and supportive wife, and two wonderful daughters. He can be found on Twitter @SimonTualChalot.

    更新日期:2020-01-17
  • Activated Endothelial TGFβ1 Signaling Promotes Venous Thrombus Nonresolution in Mice Via Endothelin-1
    Circ. Res. (IF 15.862) Pub Date : 2019-11-21
    Magdalena L. Bochenek; Christiane Leidinger; Nico S. Rosinus; Rajinikanth Gogiraju; Stefan Guth; Lukas Hobohm; Kerstin Jurk; Eckhard Mayer; Thomas Münzel; Mareike Lankeit; Markus Bosmann; Stavros Konstantinides; Katrin Schäfer

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    更新日期:2020-01-17
  • Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesis
    Circ. Res. (IF 15.862) Pub Date : 2019-11-11
    Julia Ritterhoff; Sara Young; Outi Villet; Dan Shao; F. Carnevale Neto; Lisa F. Bettcher; Yun-Wei A. Hsu; Stephen C. Kolwicz Jr; Daniel Raftery; Rong Tian

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    更新日期:2020-01-17
  • Monogenic and Polygenic Contributions to Atrial Fibrillation Risk
    Circ. Res. (IF 15.862) Pub Date : 2019-11-06
    Seung Hoan Choi; Sean J. Jurgens; Lu-Chen Weng; James P. Pirruccello; Carolina Roselli; Mark Chaffin; Christina J.-Y. Lee; Amelia W. Hall; Amit V. Khera; Kathryn L. Lunetta; Steven A. Lubitz; Patrick T. Ellinor

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    更新日期:2020-01-17
  • miRNA-Mediated Suppression of a Cardioprotective Cardiokine as a Novel Mechanism Exacerbating Post-MI Remodeling by Sleep Breathing Disorders
    Circ. Res. (IF 15.862) Pub Date : 2019-11-07
    Yunhui Du; Xiao Wang; Linyi Li; Wenjing Hao; Huina Zhang; Yu Li; Yanwen Qin; Shaoping Nie; Theodore A. Christopher; Bernard L. Lopez; Wayne Bond Lau; Yajing Wang; Xin-Liang Ma; Yongxiang Wei

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    更新日期:2020-01-17
  • Loss of Endothelial FTO Antagonizes Obesity-Induced Metabolic and Vascular Dysfunction
    Circ. Res. (IF 15.862) Pub Date : 2019-12-05
    Nenja Krüger; Lauren A. Biwer; Miranda E. Good; Claire A. Ruddiman; Abigail G. Wolpe; Leon J. DeLalio; Sara Murphy; Edgar H. Macal Jr; Louis Ragolia; Vlad Serbulea; Angela K. Best; Norbert Leitinger; Thurl E. Harris; Swapnil K. Sonkusare; Axel Gödecke; Brant E. Isakson

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    更新日期:2020-01-17
  • Loss of Endothelial Endoglin Promotes High-Output Heart Failure Through Peripheral Arteriovenous Shunting Driven by VEGF Signaling
    Circ. Res. (IF 15.862) Pub Date : 2019-12-06
    Simon Tual-Chalot; Maria Garcia-Collado; Rachael E. Redgrave; Esha Singh; Benjamin Davison; Catherine Park; Hua Lin; Saimir Luli; Yi Jin; Yixin Wang; Allan Lawrie; Lars Jakobsson; Helen M. Arthur

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    更新日期:2020-01-17
  • Chronobiological Influence Over Cardiovascular Function
    Circ. Res. (IF 15.862) Pub Date : 2020-01-16
    Samir Rana; Sumanth D. Prabhu; Martin E. Young

    Essentially all biological processes fluctuate over the course of the day, observed at cellular (eg, transcription, translation, and signaling), organ (eg, contractility and metabolism), and whole-body (eg, physical activity and appetite) levels. It is, therefore, not surprising that both cardiovascular physiology (eg, heart rate and blood pressure) and pathophysiology (eg, onset of adverse cardiovascular events) oscillate during the 24-hour day. Chronobiological influence over biological processes involves a complex interaction of factors that are extrinsic (eg, neurohumoral factors) and intrinsic (eg, circadian clocks) to cells. Here, we focus on circadian governance of 6 fundamentally important processes: metabolism, signaling, electrophysiology, extracellular matrix, clotting, and inflammation. In each case, we discuss (1) the physiological significance for circadian regulation of these processes (ie, the good); (2) the pathological consequence of circadian governance impairment (ie, the bad); and (3) whether persistence/augmentation of circadian influences contribute to pathogenesis during distinct disease states (ie, the ugly). Finally, the translational impact of chronobiology on cardiovascular disease is highlighted.

    更新日期:2020-01-17
  • Role of Mitochondrial Calcium and the Permeability Transition Pore in Regulating Cell Death
    Circ. Res. (IF 15.862) Pub Date : 2020-01-16
    Tyler M. Bauer; Elizabeth Murphy

    Adult cardiomyocytes are postmitotic cells that undergo very limited cell division. Thus, cardiomyocyte death as occurs during myocardial infarction has very detrimental consequences for the heart. Mitochondria have emerged as an important regulator of cardiovascular health and disease. Mitochondria are well established as bioenergetic hubs for generating ATP but have also been shown to regulate cell death pathways. Indeed many of the same signals used to regulate metabolism and ATP production, such as calcium and reactive oxygen species, are also key regulators of mitochondrial cell death pathways. It is widely hypothesized that an increase in calcium and reactive oxygen species activate a large conductance channel in the inner mitochondrial membrane known as the PTP (permeability transition pore) and that opening of this pore leads to necroptosis, a regulated form of necrotic cell death. Strategies to reduce PTP opening either by inhibition of PTP or inhibiting the rise in mitochondrial calcium or reactive oxygen species that activate PTP have been proposed. A major limitation of inhibiting the PTP is the lack of knowledge about the identity of the protein(s) that form the PTP and how they are activated by calcium and reactive oxygen species. This review will critically evaluate the candidates for the pore-forming unit of the PTP and discuss recent data suggesting that assumption that the PTP is formed by a single molecular identity may need to be reconsidered.

    更新日期:2020-01-17
  • Sympathetic Enhancement of Memory T Cell Homing and Hypertension Sensitization
    Circ. Res. (IF 15.862) Pub Date : 2020-01-13
    Liang Xiao; Luciana Do Carmo; Jason D Foss; Wei Chen; David G Harrison

    Rationale: Effector memory T lymphocytes (TEM cells) exacerbate hypertension in response to repeated hypertensive stimuli. These cells reside in the bone marrow for prolonged periods and can be reactivated upon re-exposure to the hypertensive stimulus.Objective: Because hypertension is associated with increased sympathetic outflow to the bone marrow, we hypothesized that sympathetic nerves regulate accumulation and reactivation of bone marrow residing hypertension-specific TEM cells.Methods and Results: Using unilateral superior cervical ganglionectomy in wild-type C57BL/6 mice, we showed that sympathetic nerves create a bone marrow environment that supports residence of hypertension-specific CD8+ T cells. These cells, defined by their proliferative response upon co-culture with dendritic cells from angiotensin II infused mice, were reduced in denervated compared to innervated bone of angiotensin II-infused mice. Adoptively transferred CD8+ T cells from angiotensin II-infused mice preferentially homed to innervated compared to denervated bone. In contrast, ovalbumin responsive T cells from OT-I mice did not exhibit this preferential homing. Increasing superior cervical ganglion activity by activating Gq-coupled DREADD (designer receptor exclusively activated by designer drug) augmented CD8+ TEM bone marrow accumulation. Adoptive transfer studies using mice lacking β2 adrenergic receptors (β2AR) indicate that β2AR in the bone marrow niche, rather than T cell β2AR is critical for TEM cell homing. Inhibition of global sympathetic outflow using Gi-coupled DREADD injected into the rostral ventrolateral medulla or treatment with a β2AR antagonist reduced hypertension specific CD8+ TEM cells in the bone marrow and reduced the hypertensive response to a subsequent response to low dose angiotensin II.Conclusions: Sympathetic nerves contribute to the homing and survival of hypertension-specific TEM cells in the bone marrow after they are formed in hypertension. Inhibition of sympathetic nerve activity and β2AR blockade reduces these cells and prevents the blood pressure elevation and renal inflammation upon re-exposure to hypertension stimuli.

    更新日期:2020-01-13
  • Three-Dimensional Imaging Provides Detailed Atherosclerotic Plaque Morphology and Reveals Angiogenesis after Carotid Artery Ligation
    Circ. Res. (IF 15.862) Pub Date : 2020-01-09
    Tobias Becher; Dario F Riascos-Bernal; Daniel J Kramer; Vanessa Almonte; Jingyi Chi; Tao Tong; Gustavo H Oliveira-Paula; Issam Koleilat; Wei Chen; Paul Cohen; Nicholas ES Sibinga

    Rationale: Remodeling of the vessel wall and the formation of vascular networks are dynamic processes that occur during mammalian embryonic development and in adulthood. Plaque development and excessive neointima formation are hallmarks of atherosclerosis and vascular injury. As our understanding of these complex processes evolves, there is a need to develop new imaging techniques to study underlying mechanisms.Objective: We used tissue clearing and light-sheet microscopy for three-dimensional (3D) profiling of the vascular response to carotid artery ligation and induction of atherosclerosis in mouse models.Methods and Results: Adipo-Clear and immunolabeling in combination with light-sheet microscopy were applied to image carotid arteries (CAs) and brachiocephalic arteries (BCAs), allowing for 3D reconstruction of vessel architecture. Entire 3D neointima formations with different geometries were observed within the CA and scored by volumetric analysis. Additionally, we identified a CD31-positive adventitial plexus after ligation of the CA that evolved and matured over time. We also used this method to characterize plaque extent and composition in the BCA of ApoE-deficient mice on high-fat diet. The plaques exhibited inter-animal differences in terms of plaque volume, geometry, and ratio of acellular core to plaque volume. A 3D reconstruction of the endothelium overlying the plaque was also generated.Conclusions: We present a novel approach to characterize vascular remodeling in adult mice using Adipo-Clear in combination with light-sheet microscopy. Our method reconstructs 3D neointima formation after arterial injury and allows for volumetric analysis of remodeling, in addition to revealing angiogenesis and maturation of a plexus surrounding the CA. This method generates complete 3D reconstructions of atherosclerotic plaques and uncovers their volume, geometry, acellular component, surface, and spatial position within the BCA. Our approach may be used in a number of mouse models of cardiovascular disease to assess vessel geometry and volume.

    更新日期:2020-01-09
  • Enhanced CaMKII-Dependent Late INa Induces Atrial Pro-Arrhythmic Activity in Patients with Sleep-Disordered Breathing
    Circ. Res. (IF 15.862) Pub Date : 2020-01-06
    Simon Lebek; Konstantin Pichler; Kathrin Reuthner; Maximilian Trum; Maria Tafelmeier; Julian Mustroph; d=Daniele camboni; Leopold Rupprecht; Christof Schmid; Lars S Maier; Michael Arzt; Stefan Wagner

    Rationale: Sleep-disordered breathing (SDB) is frequently associated with atrial arrhythmias. Increased Ca/calmodulin-dependent protein kinase II (CaMKII) activity has been previously implicated in atrial arrhythmogenesis.Objective: We hypothesized that CaMKII-dependent dysregulation of Na current (INa) may contribute to atrial pro-arrhythmic activity in SDB patients.Methods and Results: We prospectively enrolled 113 patients undergoing elective coronary artery bypass grafting for cross-sectional study and collected right atrial appendage biopsies. The presence of SDB (defined as apnea-hypopnea index, AHI {greater than or equal to}15/h) was assessed with a portable SDB monitor the night before surgery. Compared to 56 patients without SDB, patients with SDB (57) showed a significantly increased level of activated CaMKII. Patch clamp was used to measure INa. There was a significantly enhanced late INa but reduced peak INa due to enhanced steady-state inactivation in atrial myocytes of patients with SDB consistent with significantly increased CaMKII-dependent cardiac Na channel phosphorylation (NaV1.5, at serine 571, Western blotting). These gating changes could be fully reversed by acute CaMKII inhibition (AIP). As a consequence, we observed significantly more cellular afterdepolarizations and more severe premature atrial contractions (PACs) in atrial trabeculae of SDB patients, which could be blocked by either AIP or KN93. In multivariable linear regression models incorporating age, gender, body mass index, existing AF, existing heart failure, diabetes and creatinine levels, AHI was independently associated with increased CaMKII activity, enhanced late INa and correlated with PAC severity.Conclusions: In atrial myocardium of SDB patients, increased CaMKII-dependent phosphorylation of NaV1.5 results in dysregulation of INa with pro-arrhythmic activity that was independent from pre-existing co-morbidities. Inhibition of CaMKII may be useful for prevention or treatment of arrhythmias in SDB.

    更新日期:2020-01-06
  • In This Issue
    Circ. Res. (IF 15.862) Pub Date : 2020-01-02
    Ruth Williams

    In addition to excessive lipids in the blood, inflammation is a key driver of atherosclerosis. Indeed, plaques grow as a result of fatty deposits and the accumulation and proliferation of monocytes and macrophages in the vessel walls. In mice, such proliferation can be inhibited by the systemic administration of the immunosuppressive compound rapamycin. However, because such treatment can cause toxic side effects, researchers are investigating tissue-localized delivery methods. One such approach suggested by Boada and colleagues is to use rapamycin-loaded leukosomes—nanoparticles encapsulated in a lipid coating containing leukocyte membrane proteins. The coating enables the particles to mimic leukocyte homing such that they accumulate at atherosclerotic plaques. And now the team has shown that with a rapamycin payload, the particles reduce plaque macrophage proliferation better than systemic administration of the drug. Following 7 days of once-daily rapamycin-leukosome administration, plaque burden in atherosclerosis model mice was significantly lower than in control animals. Importantly, no toxicity was detected. These proof-of-principle results now set the stage for further testing in larger, clinically relevant animals, say the authors. In the body, essential fatty acids, such as those found in fish oils, are converted into specialized proresolving mediators (SPMs)—molecules that promote phagocytosis of dead cells and reduce inflammation. Whether taking such oils reduces vascular inflammation in people, however, is unclear. Some studies show the oils reduce inflammation, others show no effect. One problem is that there is no impartial measure of the clinical efficacy of such supplementation. Souza and colleagues, therefore, performed a double-blind, placebo-controlled study to determine the effects of marine oil supplementation on both SPM levels and immune cell function. Twenty-two volunteers were randomly assigned to receive placebo or 1 of 3 doses of marine oil. Blood samples from the subjects revealed a dose-dependent increase in SPMs that was significant in the 2 high-dose groups and peaked a few hours after dosing. The team went on to show that, in the high-dose blood samples, monocytes and neutrophils had increased phagocytic activity while leukocyte activation was decreased. These effects persisted after SPM levels returned to baseline. The results suggest SPMs are not only likely mediators of fatty acid-induced immune effects but that they could be useful efficacy indicators for future trials. A high level of triglycerides in the blood is a marker of cardiometabolic disease—a collection of symptoms including insulin resistance, obesity, dyslipidemia, and hypertension. However, this correlation does not occur in people of African ancestry. Indeed, black individuals may have apparently low triglyceride levels even when symptoms of cardiometabolic disease are present. To get to the bottom of this paradox, Chung and colleagues examined triglycerides in blood samples from black and white women to see if a specific subfraction of the lipoproteins—based on particle size—might correlate with symptoms. Women (122) of similar ages, body mass indices, and backgrounds had blood samples collected for insulin sensitivity tests and triglyceride measurements. The team found that while levels of large, medium, and small triglycerides were lower in blacks than whites regardless of insulin sensitivity, levels of very small triglycerides, which are known to be proatherogenic, did correlate with insulin sensitivity in both racial groups. The findings could not only form the basis of more accurate triglyceride tests for assessing cardiovascular disease severity in all races, but also highlight the potential importance of very small triglycerides in contributing to the progression of the condition.

    更新日期:2020-01-04
  • Meet the First Author
    Circ. Res. (IF 15.862) Pub Date : 2020-01-02

    Eric Schoger graduated from the University of Goettingen, Germany, with a BS in Molecular Medicine and MS in Cardiovascular Science and is currently a PhD student in Laura Zelarayan’s laboratory at the University Medical Center Goettingen. He joined Dr Zelarayan’s group during his undergraduate studies and investigated heart-specific regulators of Wnt/beta-catenin signaling in the embryonic and adult heart. For his master’s thesis, he joined Eric Olson’s laboratory at UT Southwestern to establish the cardiomyocyte-specific CRISPRa mouse model as a collaborative project. With this tool, he continues to activate gene programs to identify targets preventing heart failure progression. In his free time, he enjoys travelling, volunteers at the Red Cross, and tries to master his cooking skills. He can be found on Twitter @schogerandspice. Christian Boada is finishing up his PhD at Monterrey Tec in Mexico, where he also earned his BA in biosciences. His graduate work mainly focused on the application of biomimetic nanoparticles for the treatment of cardiovascular diseases. He is currently working as a postgraduate associate at Duke University, focusing on the application of biomimetic nanoparticles towards achieving long-term transplant tolerance. Christian’s research interests include nanotechonology, cardiovascular disease, and the investigation of immunological modulation by biomimetic particles. The manuscript in this issue represents the culmination of a long road that begun as a single experiment (inherited from a departing lab member) that was met with a lot of skepticism initially. In addition to his research, Christian enjoys exploring the intersection between art and science, as well as scientific illustration, providing cover images as well as figures for colleagues. Some of his work can be found at vizualscientist.com. He can be found on Twitter @VizualScientist. Dr Felipe Paredes grew up in the south of Chile, where he earned a BS in Biochemistry from the University of Conception. Later, he earned his PhD in Biochemistry from the University of Chile, focusing on understanding the role of endoplasmic reticulum oxidative stress in the regulation of mitochondrial function. In 2016, he moved to the US where he began working in the laboratory of Dr Alejandra San Martin in the Division of Cardiology at Emory University in Atlanta. During his tenure as a postdoctoral fellow, Dr Paredes has worked on elucidating the role of the mitochondrial protein Poldip2 in the regulation of bioenergetics and cell metabolism. He is passionate about the lab and his main research interest is in exploring the connection between proteasome function and the regulation of metabolism. Outside of the laboratory, Felipe loves to cook and spend time with his family and their new puppy, Picadillo. Dr Anja Karlstaedt is currently a Postdoctoral Research Fellow in the Division of Cardiology, McGovern Medical School at the University of Texas Health Science Center at Houston. Dr Karlstaedt earned her doctoral and medical degrees from the Charité – Universitätsmedizin Berlin in Germany, where she worked in the laboratories of Dr Hermann-Georg Holzhütter and Dr Vera Regitz-Zagrosek focusing on the metabolic stress response in the heart. She developed CardioNet (Karlstädt et al, 2012), the first genome-scale metabolic network of mammalian cardiac metabolism. In 2014, Dr Karlstaedt joined the laboratory of Dr Heinrich Taegtmeyer at McGovern Medical School, renowned for its expertise in cardiac metabolism and isolated working heart perfusions. Using systems biology approaches, she discovered that the oncometabolite D-2-hydroxyglutarate causes contractile dysfunction and epigenetic remodelling in the heart. With the support of an NIH Pathway to Independence Award (K99/R00), she wants to establish her own laboratory to study how metabolic stress derived from cancers drives the development of heart failure. Her goal is to develop therapeutic strategies that target the tumour while protecting the heart. In her spare time, Dr Karlstaedt enjoys playing the cello, learning new languages (she already speaks Danish and Japanese), and building robots using Raspberry Pi. Dr Patricia R. Souza earned her MS in 2012 from the Federal University of Minas Gerais/Brazil. In 2013, she started her PhD at WHRI/United Kingdom (mentor, Dr Mauro Perretti). Soon after earning her doctoral degree, she joined Dr Jesmond Dalli’s team to investigate the role of specialized proresolving mediators (SPM) in regulating innate and adaptive immune responses in rheumatoid arthritis and cardiovascular disease. Patricia loves the idea that one day she will be part of a discovery that will help transform the lives of people living with chronic inflammatory disorders. In the meantime, together with her beloved husband, she is focused on helping their daughter discover a new world every day. Dr Raquel Marques is a biochemist specializing in immunology. She earned her BS in 2007 from the Faculty of Science, University of Porto, Portugal. In 2014, she completed her PhD with a focus on the molecular and cellular immune mechanisms in the pathogenesis of Rabbit Haemorrhagic Disease at the Institute of Biomedical Sciences Abel Salazar, University of Porto, under the supervision of Dr Paula Ferreira Proença. She then moved to the Unit for Multidisciplinary Research in Biomedicine, University of Porto, where she focused on mechanisms involved in the resolution of inflammation and how these become disrupted in chronic inflammatory conditions. In 2016, she moved to London to join Dr Jesmond Dalli and his team at William Harvey Research Institute, the Barts and The London School of Medicine and Dentistry and Queen Mary College. Since then her work has been focused on the role of proresolving mediators in regulating both innate and adaptive immunity. Dr Stephanie T. Chung is originally from Kingston, Jamaica. She is a board-certified internist and pediatric endocrinologist, Co-Director of the Metabolic Research Unit in the Intramural Program of the National Institute of Diabetes, Digestive, and Kidney Diseases at the National Institutes of Health, and Adjunct Assistant Professor of Pediatrics at The George Washington University School of Medicine. She earned her M.B.B.S(Hons) from the University of the West Indies Medical School, completed her residency training at the University of Texas Medical Branch in Galveston, and her fellowship training at Baylor College of Medicine in Houston. Her combined clinical and research goals are to reduce diabetes health disparities across the lifespan by improving diabetes risk stratification and management, especially in women and underrepresented minority populations. Throughout her early career as a physician scientist, she has been a staunch advocate and mentor for aspiring young scientists from all backgrounds. Though often elusive, she strives to achieve work-life balance and enjoys running, hiking, and baking with her three children.

    更新日期:2020-01-04
  • CRISPR-Mediated Activation of Endogenous Gene Expression in the Postnatal Heart
    Circ. Res. (IF 15.862) Pub Date : 2019-11-15
    Eric Schoger; Kelli J. Carroll; Lavanya M. Iyer; John R. McAnally; Wei Tan; Ning Liu; Claudia Noack; Orr Shomroni; Gabriela Salinas; Julia Groß; Nicole Herzog; Shirin Doroudgar; Rhonda Bassel-Duby; Wolfram-H. Zimmermann; Laura C. Zelarayán

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    更新日期:2020-01-04
  • Rapamycin-Loaded Biomimetic Nanoparticles Reverse Vascular Inflammation
    Circ. Res. (IF 15.862) Pub Date : 2019-10-24
    Christian Boada; Assaf Zinger; Christopher Tsao; Picheng Zhao; Jonathan O. Martinez; Kelly Hartman; Tomoyuki Naoi; Roman Sukhoveshin; Manuela Sushnitha; Roberto Molinaro; Barry Trachtenberg; John P. Cooke; Ennio Tasciotti

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    更新日期:2020-01-04
  • 更新日期:2020-01-04
  • Glucose 6-Phosphate Accumulates via Phosphoglucose Isomerase Inhibition in Heart Muscle
    Circ. Res. (IF 15.862) Pub Date : 2019-11-08
    Anja Karlstaedt; Radhika Khanna; Manoj Thangam; Heinrich Taegtmeyer

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    更新日期:2020-01-04
  • Enriched Marine Oil Supplements Increase Peripheral Blood Specialized Pro-Resolving Mediators Concentrations and Reprogram Host Immune Responses
    Circ. Res. (IF 15.862) Pub Date : 2019-12-12
    Patricia R. Souza; Raquel M. Marques; Esteban A. Gomez; Romain A. Colas; Roberta De Matteis; Anne Zak; Mital Patel; David J. Collier; Jesmond Dalli

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    更新日期:2020-01-04
  • Triglyceride Paradox Is Related to Lipoprotein Size, Visceral Adiposity and Stearoyl-CoA Desaturase Activity in Black Versus White Women
    Circ. Res. (IF 15.862) Pub Date : 2019-10-18
    Stephanie T. Chung; Celeste K.L. Cravalho; Abby G. Meyers; Amber B. Courville; Shanna Yang; Nirupa Rachel Matthan; Lilian Mabundo; Maureen Sampson; Ronald Ouwerkerk; Ahmed M. Gharib; Alice H. Lichtenstein; Alan T. Remaley; Anne E. Sumner

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    更新日期:2020-01-04
  • Vitamin D, Marine n-3 Fatty Acids, and Primary Prevention of Cardiovascular Disease Current Evidence
    Circ. Res. (IF 15.862) Pub Date : 2020-01-02
    JoAnn E. Manson; Shari S. Bassuk; Nancy R. Cook; I-Min Lee; Samia Mora; Christine M. Albert; Julie E. Buring; for the VITAL Research Group

    Whether marine omega-3 fatty acid (n-3 FA) or vitamin D supplementation can prevent cardiovascular disease (CVD) in general populations at usual risk for this outcome is unknown. A major goal of VITAL (Vitamin D and Omega-3 Trial) was to fill this knowledge gap. In this article, we review the results of VITAL, discuss relevant mechanistic studies regarding n-3 FAs, vitamin D, and vascular disease, and summarize recent meta-analyses of the randomized trial evidence on these agents. VITAL was a nationwide, randomized, placebo-controlled, 2×2 factorial trial of marine n-3 FAs (1 g/d) and vitamin D3 (2000 IU/d) in the primary prevention of CVD and cancer among 25 871 US men aged ≥50 and women aged ≥55 years, including 5106 blacks. Median treatment duration was 5.3 years. Supplemental n-3 FAs did not significantly reduce the primary cardiovascular end point of major CVD events (composite of myocardial infarction, stroke, and CVD mortality; hazard ratio [HR], 0.92 [95% CI, 0.80–1.06]) but were associated with significant reductions in total myocardial infarction (HR, 0.72 [95% CI, 0.59–0.90]), percutaneous coronary intervention (HR, 0.78 [95% CI, 0.63–0.95]), and fatal myocardial infarction (HR, 0.50 [95% CI, 0.26–0.97]) but not stroke or other cardiovascular end points. For major CVD events, a treatment benefit was seen in those with dietary fish intake below the cohort median of 1.5 servings/wk (HR, 0.81 [95% CI, 0.67–0.98]) but not in those above (P interaction=0.045). For myocardial infarction, the greatest risk reductions were in blacks (HR, 0.23 [95% CI, 0.11–0.47]; P interaction by race, 0.001). Vitamin D supplementation did not reduce major CVD events (HR, 0.97 [95% CI, 0.85–1.12]) or other cardiovascular end points. Updated meta-analyses that include VITAL and other recent trials document coronary risk reduction from supplemental marine n-3 FAs but no clear CVD risk reduction from supplemental vitamin D. Additional research is needed to determine which individuals may be most likely to derive net benefit from supplementation.Clinical Trial Registration:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01169259.

    更新日期:2020-01-04
  • Role of Nitric Oxide Carried by Hemoglobin in Cardiovascular Physiology
    Circ. Res. (IF 15.862) Pub Date : 2019-10-08
    Richard T. Premont; James D. Reynolds; Rongli Zhang; Jonathan S. Stamler

    A continuous supply of oxygen is essential for the survival of multicellular organisms. The understanding of how this supply is regulated in the microvasculature has evolved from viewing erythrocytes (red blood cells [RBCs]) as passive carriers of oxygen to recognizing the complex interplay between Hb (hemoglobin) and oxygen, carbon dioxide, and nitric oxide—the three-gas respiratory cycle—that insures adequate oxygen and nutrient delivery to meet local metabolic demand. In this context, it is blood flow and not blood oxygen content that is the main driver of tissue oxygenation by RBCs. Herein, we review the lines of experimentation that led to this understanding of RBC function; from the foundational understanding of allosteric regulation of oxygen binding in Hb in the stereochemical model of Perutz, to blood flow autoregulation (hypoxic vasodilation governing oxygen delivery) observed by Guyton, to current understanding that centers on S-nitrosylation of Hb (ie, S-nitrosohemoglobin; SNO-Hb) as a purveyor of oxygen-dependent vasodilatory activity. Notably, hypoxic vasodilation is recapitulated by native S-nitrosothiol (SNO)–replete RBCs and by SNO-Hb itself, whereby SNO is released from Hb and RBCs during deoxygenation, in proportion to the degree of Hb deoxygenation, to regulate vessels directly. In addition, we discuss how dysregulation of this system through genetic mutation in Hb or through disease is a common factor in oxygenation pathologies resulting from microcirculatory impairment, including sickle cell disease, ischemic heart disease, and heart failure. We then conclude by identifying potential therapeutic interventions to correct deficits in RBC-mediated vasodilation to improve oxygen delivery—steps toward effective microvasculature-targeted therapies. To the extent that diseases of the heart, lungs, and blood are associated with impaired tissue oxygenation, the development of new therapies based on the three-gas respiratory system have the potential to improve the well-being of millions of patients.

    更新日期:2020-01-04
  • PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling
    Circ. Res. (IF 15.862) Pub Date : 2020-01-02
    Urszula Rykaczewska; Bianca E Suur; Samuel Röhl; Anton Razuvaev; Mariette Lengquist; Maria Sabater-Lleal; Sander W van der Laan; Clint L Miller; Robert C Wirka; Malin Kronqvist; Maria Gonzalez Diez; Mattias Vesterlund; Peter Gillgren; Jacob Odeberg; Jan HN Lindeman; Fabrizio Veglia; Steve E Humphries; Ulf de Faire; Damiano Baldassarre; Elena Tremoli; Janne Lehtiö; Göran K Hansson; Gabrielle Paulsson-Berne; Gerard Pasterkamp; Thomas Quertermous; Anders Hamsten; Per Eriksson; Ulf Hedin; Ljubica Matic

    Rationale: Proprotein convertase subtilisins/kexins (PCSKs) are a protease family with unknown functions in vasculature. Previously, we demonstrated PCSK6 upregulation in human atherosclerotic plaques associated with smooth muscle cells (SMCs), inflammation, extracellular matrix (ECM) remodeling and mitogens.Objective: Here, we applied a systems biology approach to gain deeper insights into the PCSK6 role in normal and diseased vessel wall.Methods and Results: Genetic analyses revealed association of intronic PCSK6 variant rs1531817 with maximum internal carotid intima-media thickness progression in high-cardiovascular risk subjects. This variant was linked with PCSK6 mRNA expression in healthy aortas and plaques, but also with overall plaque SMA+ cell content and pericyte fraction. Increased PCSK6 expression was found in several independent human cohorts comparing atherosclerotic lesions vs. healthy arteries, using transcriptomic and proteomic datasets. By immunohistochemistry, PCSK6 was localised to fibrous cap SMA+ cells and neovessels in plaques. In human, rat, and mouse intimal hyperplasia, PCSK6 was expressed by proliferating SMA+ cells and upregulated after 5 days in rat carotid balloon injury model, with positive correlation to PDGFB and MMP2/MMP14. Here, PCSK6 was shown to co-localise and co-interact with MMP2/MMP14 by in situ proximity ligation assay. Microarrays of carotid arteries from Pcsk6-/- vs. control mice revealed suppression of contractile SMC markers, ECM remodeling enzymes and cytokines/receptors. Pcsk6-/- mice showed reduced intimal hyperplasia response upon carotid ligation in vivo, accompanied by decreased MMP14 activation and impaired SMC outgrowth from aortic rings ex vivo. PCSK6 silencing in human SMCs in vitro lead to downregulation of contractile markers and increase in MMP2 expression. Conversely, PCSK6 overexpression increased PDGFBB-induced cell proliferation and particularly migration.Conclusions: PCSK6 is a novel protease that induces SMC migration in response to PDGFB, mechanistically via modulation of contractile markers and MMP14 activation. This study establishes PCSK6 as a key regulator of SMC function in vascular remodeling.

    更新日期:2020-01-02
  • In This Issue.
    Circ. Res. (IF 15.862) Pub Date : 2017
    R. Lloyd Williams

    更新日期:2020-01-01
  • 更新日期:2020-01-01
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