Blood Biomarkers in Takotsubo Syndrome Point to an Emerging Role for Inflammaging in Endothelial Pathophysiology

Takotsubo syndrome (TTS), an acute cardiac condition characterized by transient wall motion abnormalities mostly of the left ventricle, results in difficulties in diagnosing patients. We set out to present a detailed blood analysis of TTS patients analyzing novel markers to understand the development of TTS. Significant differences in proinflammatory cytokine expression patterns and sex steroid and glucocorticoid receptor (GR) expression levels were observed in the TTS patient collected. Remarkably, the measured catecholamine serum concentrations determined from TTS patient blood could be shown to be two orders of magnitude lower than the levels determined from experimentally induced TTS in laboratory animals. Consequently, the exposure of endothelial cells and cardiomyocytes in vitro to such catecholamine concentrations did not damage the cellular integrity or function of either endothelial cells forming the blood–brain barrier, endothelial cells derived from myocardium, or cardiomyocytes in vitro. Computational analysis was able to link the identified blood markers, specifically, the proinflammatory cytokines and glucocorticoid receptor GR to microRNA (miR) relevant in the ontogeny of TTS (miR-15) and inflammation (miR-21, miR-146a), respectively. Amongst the well-described risk factors of TTS (older age, female sex), inflammaging-related pathways were identified to add to these relevant risk factors or prediagnostic markers of TTS.

[1]  C. Förster,et al.  Hemorrhagic Cerebral Insults and Secondary Takotsubo Syndrome: Findings in a Novel In Vitro Model Using Human Blood Samples , 2022, International journal of molecular sciences.

[2]  S. Ergün,et al.  The Protective Effects of Neurotrophins and MicroRNA in Diabetic Retinopathy, Nephropathy and Heart Failure via Regulating Endothelial Function , 2022, Biomolecules.

[3]  C. Steinwender,et al.  Neutrophile-Lymphocyte Ratio and Outcome in Takotsubo Syndrome , 2022, Biology.

[4]  D. Newby,et al.  Renin‐Angiotensin and Endothelin Systems in Patients Post‐Takotsubo Cardiomyopathy , 2022, Journal of the American Heart Association.

[5]  G. Maróti,et al.  Expression of anti-inflammatory markers IL-2, IL-10, TGF-β1, βDEF-2, βDEF-3 and Cathelicidin LL37 in dairy cattle milk with different health status of the udder. , 2022, Polish journal of veterinary sciences.

[6]  M. Bardo,et al.  Effect of the glucocorticoid receptor antagonist PT150 on acquisition and escalation of fentanyl self-administration following early-life stress. , 2022, Experimental and clinical psychopharmacology.

[7]  N. Brunetti,et al.  Gender Differences in Takotsubo Syndrome. , 2022, Journal of the American College of Cardiology.

[8]  S. Ergün,et al.  Quantitative Lipidomic Analysis of Takotsubo Syndrome Patients' Serum , 2022, Frontiers in Cardiovascular Medicine.

[9]  S. Ullah,et al.  In-silico analysis of non-synonymous single nucleotide polymorphisms in human β-defensin type 1 gene reveals their impact on protein-ligand binding sites , 2022, Comput. Biol. Chem..

[10]  Y. Ladilov,et al.  Cardiovascular Inflammaging: Mechanisms and Translational Aspects , 2022, Cells.

[11]  D. Newby,et al.  Takotsubo Syndrome: Pathophysiology, Emerging Concepts and Clinical Implications , 2022, Circulation.

[12]  A. Sica,et al.  Immunosenescence, Inflammaging, and Frailty: Role of Myeloid Cells in Age-Related Diseases , 2022, Clinical Reviews in Allergy & Immunology.

[13]  C. Förster,et al.  Sex Hormone-Specific Neuroanatomy of Takotsubo Syndrome: Is the Insular Cortex a Moderator? , 2022, Biomolecules.

[14]  Varun Pattisapu,et al.  Sex‐ and Age‐Based Temporal Trends in Takotsubo Syndrome Incidence in the United States , 2021, Journal of the American Heart Association.

[15]  Ç. Demirdağ,et al.  The clinical significance of circulating miR-21, miR-142, miR-143, and miR-146a in patients with prostate cancer , 2021, Journal of medical biochemistry.

[16]  K. Cederlund,et al.  Plasma catecholamine levels in the acute and subacute stages of takotsubo syndrome: Results from the Stockholm myocardial infarction with normal coronaries 2 study , 2021, Clinical cardiology.

[17]  E. Onrat,et al.  Investigating changes in β-adrenergic gene expression (ADRB1 and ADRB2) in Takotsubo (stress) cardiomyopathy syndrome; a pilot study , 2021, Molecular Biology Reports.

[18]  Jeroen J. Bax,et al.  Impact of Atrial Fibrillation on Outcome in Takotsubo Syndrome: Data From the International Takotsubo Registry , 2021, Journal of the American Heart Association.

[19]  S. Harding,et al.  Circulating microRNAs predispose to takotsubo syndrome following high-dose adrenaline exposure , 2021, Cardiovascular research.

[20]  A. Marsland,et al.  Glucocorticoid resistance and β2-adrenergic receptor signaling pathways promote peripheral pro-inflammatory conditions associated with chronic psychological stress: A systematic review across species , 2021, Neuroscience & Biobehavioral Reviews.

[21]  N. Oda,et al.  A mid‐ventricular variant of Takotsubo syndrome: was it triggered by insular cortex damage? , 2021, ESC heart failure.

[22]  D. Megías,et al.  Telomerase therapy attenuates cardiotoxic effects of doxorubicin , 2020, Molecular therapy : the journal of the American Society of Gene Therapy.

[23]  Yi-Ching Wang,et al.  MicroRNA-146a suppresses tumor malignancy via targeting vimentin in esophageal squamous cell carcinoma cells with lower fibronectin membrane assembly , 2020, Journal of Biomedical Science.

[24]  Zhao Han,et al.  1-Trifluoromethoxyphenyl-3-(1-Propionylpiperidin-4-yl) Urea Protects the Blood-Brain Barrier Against Ischemic Injury by Upregulating Tight Junction Protein Expression, Mitigating Apoptosis and Inflammation In Vivo and In Vitro Model , 2020, Frontiers in Pharmacology.

[25]  N. Oda,et al.  Happy heart syndrome: a case of Takotsubo syndrome with left internal carotid artery occlusion , 2020, Clinical Autonomic Research.

[26]  S. Störk,et al.  Increased Catecholamine Levels and Inflammatory Mediators Alter Barrier Properties of Brain Microvascular Endothelial Cells in vitro , 2020, Frontiers in Cardiovascular Medicine.

[27]  Silvia Jiménez Morales,et al.  The NR3C1 gene expression is a potential surrogate biomarker for risk and diagnosis of posttraumatic stress disorder. , 2020, Psychiatry Research.

[28]  M. Mayr,et al.  Preclinical development of a miR-132 inhibitor for heart failure treatment , 2020, Nature Communications.

[29]  D. Mann,et al.  Reappraising the role of inflammation in heart failure , 2020, Nature Reviews Cardiology.

[30]  S. Wood,et al.  The contribution of the locus coeruleus-norepinephrine system in the emergence of defeat-induced inflammatory priming , 2019, Brain, Behavior, and Immunity.

[31]  A. Henning,et al.  Myocardial and Systemic Inflammation in Acute Stress-Induced (Takotsubo) Cardiomyopathy , 2019, Circulation.

[32]  G. Horgan,et al.  Characterization of the Myocardial Inflammatory Response in Acute Stress-Induced (Takotsubo) Cardiomyopathy , 2018, JACC. Basic to translational science.

[33]  B. Spengler,et al.  Quantitative lipidomic analysis of mouse lung during postnatal development by electrospray ionization tandem mass spectrometry , 2018, PloS one.

[34]  Satoshi Okayama,et al.  Alteration of β-Adrenoceptor Signaling in Left Ventricle of Acute Phase Takotsubo Syndrome: a Human Study , 2018, Scientific Reports.

[35]  L. Ferrucci,et al.  Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty , 2018, Nature Reviews Cardiology.

[36]  C. Franceschi,et al.  Inflammaging: a new immune–metabolic viewpoint for age-related diseases , 2018, Nature Reviews Endocrinology.

[37]  N. Brunetti,et al.  Inflammatory patterns in Takotsubo cardiomyopathy and acute coronary syndrome: A propensity score matched analysis. , 2018, Atherosclerosis.

[38]  Gary D. Bader,et al.  GeneMANIA update 2018 , 2018, Nucleic Acids Res..

[39]  Jeroen J. Bax,et al.  International Expert Consensus Document on Takotsubo Syndrome (Part II): Diagnostic Workup, Outcome, and Management , 2018, European heart journal.

[40]  Jeroen J. Bax,et al.  International Expert Consensus Document on Takotsubo Syndrome (Part I): Clinical Characteristics, Diagnostic Criteria, and Pathophysiology , 2018, European heart journal.

[41]  I. Elgendy,et al.  Clinical presentations and outcomes of Takotsubo syndrome in the setting of subarachnoid hemorrhage: A systematic review and meta-analysis , 2018, European heart journal. Acute cardiovascular care.

[42]  I. Elgendy,et al.  Takotsubo syndrome: Still a benign entity? , 2017, International journal of cardiology.

[43]  Benjamin Meder,et al.  Catecholamine-Dependent β-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy. , 2017, Journal of the American College of Cardiology.

[44]  G. Göhring,et al.  Generation of non-transgenic iPS cells from human cord blood CD34+ cells under animal component-free conditions. , 2017, Stem cell research.

[45]  M. Borggrefe,et al.  Catecholamine in takotsubo syndrome. , 2017, International journal of cardiology.

[46]  T. Kakiuchi,et al.  The Role of IL-17 and Related Cytokines in Inflammatory Autoimmune Diseases , 2017, Mediators of inflammation.

[47]  A. Donato,et al.  Takotsubo cardiomyopathy associated with epinephrine use: A systematic review and meta-analysis. , 2017, International journal of cardiology.

[48]  K. Kario,et al.  The Insular Cortex and Takotsubo Cardiomyopathy. , 2017, Current pharmaceutical design.

[49]  S. Y-Hassan Divergence in the results of plasma catecholamine levels in different studies on patients with takotsubo syndrome: Why? , 2016, Journal of cardiology.

[50]  M. Robson,et al.  Pheochromocytoma Is Characterized by Catecholamine-Mediated Myocarditis, Focal and Diffuse Myocardial Fibrosis, and Myocardial Dysfunction. , 2016, Journal of the American College of Cardiology.

[51]  J. Herman,et al.  Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response. , 2016, Comprehensive Physiology.

[52]  O. Collange,et al.  Takotsubo syndrome triggered by acute intermittent porphyria attack: An unusual stressor for catecholamine-induced cardiomyopathy. , 2016, International journal of cardiology.

[53]  G. Filippatos,et al.  Current state of knowledge on Takotsubo syndrome: a Position Statement from the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology , 2016, European journal of heart failure.

[54]  J. Tobis,et al.  Is high-dose catecholamine administration in small animals an appropriate model for takotsubo syndrome? , 2015, Circulation journal : official journal of the Japanese Circulation Society.

[55]  G. Andò,et al.  Stress cardiomyopathies beyond Takotsubo: does a common catecholaminergic pathophysiology fit all? , 2014, Expert review of cardiovascular therapy.

[56]  Chris T. A. Evelo,et al.  CyTargetLinker: A Cytoscape App to Integrate Regulatory Interactions in Network Analysis , 2013, PloS one.

[57]  B. Power Faculty Opinions recommendation of High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy. , 2013 .

[58]  Hugo A. Katus,et al.  A signature of circulating microRNAs differentiates takotsubo cardiomyopathy from acute myocardial infarction , 2013, European heart journal.

[59]  Michiyasu Suzuki,et al.  Multicenter Prospective Cohort Study on Volume Management After Subarachnoid Hemorrhage: Hemodynamic Changes According to Severity of Subarachnoid Hemorrhage and Cerebral Vasospasm , 2013, Stroke.

[60]  D. Bartlett,et al.  Understanding how we age: insights into inflammaging , 2013, Longevity & healthspan.

[61]  P. Couraud,et al.  The hCMEC/D3 cell line as a model of the human blood brain barrier , 2013, Fluids and Barriers of the CNS.

[62]  Sean P. Palecek,et al.  Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions , 2012, Nature Protocols.

[63]  A. El-Sayed,et al.  Demographic and co-morbid predictors of stress (takotsubo) cardiomyopathy. , 2012, The American journal of cardiology.

[64]  C. Förster,et al.  Generation of an Immortalized Murine Brain Microvascular Endothelial Cell Line as an In Vitro Blood Brain Barrier Model , 2012, Journal of visualized experiments : JoVE.

[65]  J. Petrini,et al.  Pretreatment With Low‐Dose β‐Adrenergic Antagonist Therapy Does Not Affect Severity of Takotsubo Cardiomyopathy , 2012, Clinical cardiology.

[66]  J. Chou,et al.  Sexually Dimorphic Actions of Glucocorticoids Provide a Link to Inflammatory Diseases with Gender Differences in Prevalence , 2010, Science Signaling.

[67]  C. Croce,et al.  miR-15a and miR-16-1 in cancer: discovery, function and future perspectives , 2010, Cell Death and Differentiation.

[68]  C. Hamm,et al.  Activated cell survival cascade protects cardiomyocytes from cell death in Tako‐Tsubo cardiomyopathy , 2009, European journal of heart failure.

[69]  Marija Krstic-Demonacos,et al.  Regulation of glucocorticoid receptor activity by a stress responsive transcriptional cofactor. , 2011, Molecular endocrinology.

[70]  K. Bybee,et al.  Stress-Related Cardiomyopathy Syndromes , 2008, Circulation.

[71]  C. Förster,et al.  Dexamethasone induces the expression of metalloproteinase inhibitor TIMP‐1 in the murine cerebral vascular endothelial cell line cEND , 2007, The Journal of physiology.

[72]  R. Oberbeck Catecholamines: physiological immunomodulators during health and illness. , 2006, Current medicinal chemistry.

[73]  J. Greenwood,et al.  Blood‐brain barrier‐specific properties of a human adult brain endothelial cell line , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[74]  C. Förster,et al.  Occludin as direct target for glucocorticoid‐induced improvement of blood–brain barrier properties in a murine in vitro system , 2005, The Journal of physiology.

[75]  R. Veerhuis,et al.  How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes , 2004, Aging cell.

[76]  L. Mazzolai,et al.  Blood sampling methodology is crucial for precise measurement of plasma catecholamines concentrations in mice , 2003, Pflügers Archiv.

[77]  E. Wawrousek,et al.  Expression and induction of the stress protein alpha-B-crystallin in vascular endothelial cells , 2002, Histochemistry and Cell Biology.

[78]  B. McEwen,et al.  The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. , 1986, Endocrine reviews.

[79]  R. Kerber,et al.  Inhibition of adrenergic neurotransmission in ischaemic regions of the canine left ventricle. , 1980, Cardiovascular research.

[80]  G. Pawelec,et al.  The Immune System and Its Dysregulation with Aging. , 2019, Sub-cellular biochemistry.

[81]  S. Y-Hassan Catecholamine Levels and Cardiac Sympathetic Hyperactivation-Disruption in Takotsubo Syndrome. , 2017, JACC. Cardiovascular imaging.

[82]  J. Madias Pathophysiology of Takotsubo syndrome: an adrenergic cardiac "chemical neuritis/myocarditis"? , 2014, Cardiovascular revascularization medicine : including molecular interventions.

[83]  遠山 周吾 Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes , 2013 .

[84]  Melissa-Ann L. Scotti,et al.  Stress and neuroinflammation. , 2013, Modern trends in pharmacopsychiatry.

[85]  V. Salemi,et al.  Takotsubo cardiomyopathy triggered by β(2) adrenergic agonist. , 2011, Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia.

[86]  S. Chauvie,et al.  Reversible impairment of coronary flow reserve in takotsubo cardiomyopathy: A myocardial PET study , 2008, Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology.

[87]  C. Rihal,et al.  Electrocardiography cannot reliably differentiate transient left ventricular apical ballooning syndrome from anterior ST-segment elevation myocardial infarction. , 2007, Journal of electrocardiology.