Stress and the Heart PDF

Stress and the Heart George P Chrousos, MACP, MACE, FRCP (UK) Professor of Pediatrics and Endocrinology Emeritus National and Kapodistrian University of Athens Holder, UNESCO Chair on Adolescent Health Care Director, University Research Institute of Maternal and Child Health and Prec...

Stress and the Heart George P Chrousos, MACP, MACE, FRCP (UK) Professor of Pediatrics and Endocrinology Emeritus National and Kapodistrian University of Athens Holder, UNESCO Chair on Adolescent Health Care Director, University Research Institute of Maternal and Child Health and Precision Medicine G.P. Chrousos 2  Physical and Emotional Stress Complexity- Human Uniqueness Concepts of Homeostasis and Stress Stress Mechanisms Effects of Stress on the Organism G.P. Chrousos “Πολλά τα δεινά κ’ουδέν ανθρώπου δεινότερον πέλλει….” 'There are many wonderful things and nothing is more wonderful than the human...” Σοφοκλής Sophocles 496-406 BCE  HUMAN COMPLEXITY: POST(EPI)GENOMIC ERA Human genome: About 3+3 billion bases “Junk” now “Dark” DNA 98 vs. 2 %; of retroviral origin ~50%, 15-25K retrotransposons) About 20 thousand protein-coding genes About 24 thousand ncRNA-coding genes About 200 thousand transcripts (mRNA, ncRNA) About 200-260 thousand proteins Single nucleotide polymorphisms (snp’s or snv’s), microsatellites or copy number variants : (0.9% difference) About >25 million snp’s (snv’s), 1.5 million indels About 20 million microsatellites >5000 cnv’s (many million bases) > 100 k disease-related mutations >60% of promoters have CpG islands, >1 million reg sequences EPIGENETICS/EPIMUTATIONS  THE HUMAN BRAIN ~100 billion neurons (100x1012) x >10.000 synapses per neuron = >1018 synapses) ~ 100.000 km of fibers ~ 1 trillion or more glial cells ~ 1.25 terabytes ~ 15 Watt lamp (2% of BW uses 20% energy) Plasticity  Complex Systems “Αρμονία δ’εστί πολυμιγέων ένωσις Και δίχα φρονεόντων συμφρόνησις” “Harmony is the union of multiple mixed components and the agreement of the opposites” Αλκμαίων Κροτωνιάτης Almaeon of Croton Chaisson E, New Scientist 2009 Man and his/her civilization are of unique complexity in the known universe. Complex systems are in a dynamic disequilibrium that requires energy to be sustained. Complex systems have organizing principles and follow mathematic rules.  SYSTEMS BIOLOGY, SYSTEMS MEDICINE NARRATIVE AND PRECISION MEDICINE P4 MEDICINE (predictive, personalized, preventive, participatory)  Physical and Emotional Stress Complexity- Human Uniqueness Concepts of Homeostasis and Stress Stress Mechanisms Effects of Stress on the Organism G.P. Chrousos Pythagoras. 6th cent BCE  Complex Systems Theory Harmony Counteracting Disturbing Reestablishing Equilibrium Forces Forces Balance II II II Adaptive Stressors Homeostasis Response (Physical, Emotional) Pythagoras= Harmony Alcmaeon=Iso-nomia Hippocrates= Eucrasia Epicurus= Eustatheia Walter Cannon= Homeostasis G.P. Chrousos 12  Επικούρεια Ευστάθεια Epicurean “Eustatheia” “ευστάθεια” : “σαρκός και ψυχής ευσταθές κατάστημα” eustatheia: “the balanced state of the flesh and the soul”  Stress is the State of Threatened (or Perceived as Threatened) Homeostasis «Αρχή επιστήμης η των ονομάτων επίσκεψις» Αντισθένης “The beginning of science is the visit of names” Antisthenes  STRESS ETYMOLOGY Indoeuropean root: Gk: Strangaleuin = to strangle, also Catastrophe, and Strabismus Lt: Stringere = to draw tight, to press  STRESS CONCEPTS Pythagoras The Harmony of the Cosmos (580-489 BC) Alkmaion The intellect is based in the brain (c. 500 BC) Health is the equipose of opposing forces: «Isonomia» Empedocles Matter consists of essential elements and qualities in (500-430 BC) opposition or alliance to one another Hippocrates A harmonious balance of the elements and qualities of life (460-375 BC) is health-Dysharmony is disease, Eucrasia vs. Dyscrasia «Nouson physeis iatroi =Vis medicatrix naturae» Aristotle Unity of body and mind, “Eudaimonia” tranquil, non sensual pleasure) Stoics/Sceptics Ataraxia (imperturbability of mind, equanimity), mind controls affect Epicurus Ataraxia but also Aponia (no pain) and “Hedone” (341-270 BC) (=Eudaimonia), «Eustatheia» = Good balance, Carpe diem= seize the day Thomas Sydenham Symptoms and signs of a disease arise also from the reaction of the (AD 1624-1689 patient’s system Claude Bernard The “milieu interieur” (1813-1878) Walter Cannon Homeostasis/Stress (1871-1945) Bodily responses to emotions Fight or flight (and freeze) reactions Hans Selye The general adaptation syndrome (the stress syndrome) (1907-1982) Diseases of adaptation, Distress vs. Eustress G.P. Chrousos  Humans as Complex Biological Systems Organism Society Con(Re)sonance (“mirror” and “spindle” or von Economo neurons) “Empathy/Emotional Epidemiology”  Acute vs. Chronic Stress 19 G.P. Chrousos  Human Stressors Daily hassles Life transitions Natural and unnatural catastrophies Starvation, Excessive nutrition, Deficient exercise, Excessive exercise, Obesity Socioeconomic status, Minority status, Loneliness (Dignity) Work stress (Effort Reward Imbalance, ERI), Unemployment (Dignity) Job loss, Downsizing, Loss of control (Dignity) Social Inequality (Dignity), Social Restriction (Dignity) Bereavement Caretaking/ Pathologic empathy vs. principled compassion Addictions/ Toxic substances Chronic diseases, Treatments Inflammations (Traumatic, Infectious, Autoimmune, Allergic, Parainflammation) Anxiety, Depression, Personality disorder Sleep deficiency, Sleep excess Uncoupling of the Clock: Jet-lag, “Social-jetlag” Behavioral addictions: “Meta-modern stress” , “Cyborg stress” (“Hikikomori” disease) G.P. Chrousos “Cyborg Stress”  Homeostasis over Time Improved Homeostasis=Hyperstasis Elevated mood Healthy Baseline Homeostasis Baseline Homeostasis=Eustasis Constitutional mood Constitutional mood Deteriorated Homeostasis=Cacostasis Catabasis Suppressed mood Anabasis Distress (Eustress) 23 G.P. Chrousos  Homeostasis over Time Resilience= -Small disturbance Improved Homeostasis=Hyperstasis -Quick recovery Elevated mood Healthy Baseline Homeostasis Baseline Homeostasis=Eustasis ➔ Constitutional mood Constitutional mood Deteriorated Homeostasis=Cacostasis Catabasis Suppressed mood  Anabasis Distress/Eustress 24 G.P. Chrousos  Physical and Emotional Stress Complexity- Human Uniqueness Concepts of Homeostasis and Stress Stress Mechanisms Effects of Stress on the Organism G.P. Chrousos  Stress System NE + − CRH LC-NE ANS − + CRH 27 G.P. Chrousos Stress System Chrousos G.P. Chrousos JAMA 199228  STRESS SYSTEM Amygdala CRH HIPPOCAMPUS CRH/AVP LC/NE ACTH F NE/E GH/IGF-1 LH/T iCRH IL-6 TSH/T3 + Inflammation G.P. Chrousos  Reproduction Growth and Thyroid Function Immune Function -endorphin LHRH CRH GHRH STS CRH STS TRH CRH Cytokines LH, FSH ACTH GH ACTH TSH (TNF, IL-1, IL-6, IL-8..) ACTH T4 Testosterone, Glucocorticoids Inflammation Glucocorticoids Glucocorticoids Estradiol Mediators of SmC T3 (Eicosanoids, PAF, Serotonin) Target Tissues Target Tissues Target Tissues Target Tissues POOR GROWTH “EUTHYROID SICK” ANTI-INFLAMMATION, HYPOGONADISM Th1 to TH2 SHIFT “PARAINFLAMATION” Structures related to emotional regulation The Reward System ML MC  Acute Stress + MCLS HIPPO- AMYGDALA CAMPUS - CRH + + - + Physical Behavioral PVN adaptation CRH/AVP LC/NE adaptation Cortisol Catecholamines/IL-6 G.P. Chrousos  MC/ML System Tone + acute - - chronic Stress System Tone 35 G.P. Chrousos  Affect Behavior Development Growth Aging HPA HPA Axis Axis LC/NE System Reproductive Immune function function Biologic Clock Sleep Physical and Emotional Stress Timing (Critical periods=prenatal, first 5 y and adolescence) Acuity Chronicity G.P. Chrousos  No. of synapses/2-Deoxyglucose uptake THE DEVELOPING BRAIN Birth 2y Puberty Adulthood G.P. Chrousos Cognitive and Language Development  Prefrontal/Frontal Lobe “Higher Functions” Interpretation of the environment, social cues Problem solving Planning for the future Proper control of impulses (emotional auto-regulation)  “CRITICAL” PERIODS OF LIFE Prenatal, Early Childhood, Puberty (Human brain ontogeny complete at 25-27 y) “Organizational” Effects of Hormones, Epigenetics, “Predictive programming” (CRH, glucocorticoids, sex steroids, cytokines) 42 G.P. Chrousos  IMMUNE STRESS: INFLAMMATORY (SICKNESS) SYNDROME ANOREXIA/NAUSEA FATIGUE AND/OR DEPRESSED AFFECT SOMNOLENCE HYPERALGESIA ± HEADACHE ELEVATED TEMPERATURE/ FEVER INCREASED METABOLIC RATE MOLECULAR EFFECTORS INFLAMMATORY CYTOKINES/MEDIATORS G.P. Chrousos 43  INFLAMMATORY STRESS SICKNESS SYNDROME CLASSIC STRESS SYNDROME ANOREXIA/NAUSEA ANOREXIA/ + APPETITE* FATIGUE AND/OR DEPRESSED AFFECT MOTIVATION/STIMULATED AFFECT SOMNOLENCE HYPERALGESIA ± HEADACHE AROUSAL ELEVATED TEMPERATURE/ FEVER ANALGESIA INCREASED METABOLIC RATE PYRETIC/ANTIPYRETIC* INCREASED METABOLIC RATE/ RETURN ACUTE PHASE REACTION +++++ TO NORMAL* ACUTE PHASE REACTION+ MOLECULAR EFFECTORS INFLAMMATORY CYTOKINES/MEDIATORS CRH, AVP, GLUCOCORTICOIDS, CATECHOLAMINES, IMMUNE CRH * Initially stimulation via CRH and catecholamines; then inhibition by glucocorticoids Inflammatory (Sickness) Stress Fatigue Syndrome Syndrome Pain/Neural Afferent Program Sickness Stress Behavior Syndrome Acute Phase Reaction G.P. Chrousos 45  Alterations in Stress +/- Central Secretion Peripheral Immune Neurochemical of Cytokines Sickness Syndrome Activation and Systems (TNF, IL-1, Manifestations Cytokine Secretion (NE, 5-HT, IL-6, etc.) CRH, etc.) Post Peripheral Stress Autoimmune Neurodegenerative Stroke, Intracerebral Partum Infections Disease Disease Trauma Infections Period  Physical and Emotional Stress Complexity- Human Uniqueness Concepts of Homeostasis and Stress Stress Mechanisms Effects of Stress on the Organism G.P. Chrousos  Acute Stress Stress Hyper-responsive Child/Adult + + HIPPO- MCLS CAMPUS HIPPO- AMYGDALA AMYGDALA MCLS CAMPUS - CRH - CRH - + + + - + - + PVN PVN CRH/AVP CRH/AVP LC/NE LC/NE Cortisol + Catecholamines/IL-6 Cortisol + Catecholamines/IL-6 Behavioral consequences + Somatic consequences Maladjustment disorders Growth retardation Adjusment vs. Anxiety, Depression Metabolic syndrome X Maladjustment Personality disorders Cardiovascular disease Addiction, Psychosomatics Osteoporosis G.P. Chrousos Sickness s.  THE STRESS SYSTEM Pathophysiology Acute effects of stress system activation Asthma, eczema, urticaria Migraine and tension headache Gastrointestinal pain Hypertensive episode, CVA, Death (compromised host) Cardiac ischemia, MI, Arrhythmia, Death (compromised host), Heart failure (Takotsubo disease) Psychotic episode 49 G.P. Chrousos Takotsubo Disease Karalis et al. Science 1999 Theoharidis et al. Endo 1995  THE STRESS SYSTEM Pathophysiology 55 G.P. Chrousos  DEVELOPMENTAL HISTORY STRESS Real or perceived GENETIC VARIATION NUTRITION AGING Stress system CRH/AVP-LC/NE Systemic Sympathetic HPA axis Adrenomedullary Systems GH/IGF-1 LH, T, E2 TSH, T3 Cortisol Target Tissues NE, E, IL-6 Insulin resistance Visceral Obesity/Sarcopenia =Metabolic TG ABP Sickness Syndrome, DM type2 LDL Syndrome HDL APR Dyscoagulation Cytokines Sleep Apnea Osteoporosis PCOS Endothelial Dysfunction/Inflammation Atherosclerosis Cardiovascular Disease 56 G.P. Chrousos  Both IL-6 and TNF correlate with BMI 12 5 TNF (pg/ml) IL-6 (pg/ml) 10 4 8 3 6 2 4 r =.790 r =.400 1 2 p =.014 p =.000 0 0 20 30 40 50 60 20 30 40 50 60 BMI Vgontzas et al. JCEM 1997 HYPERCYTOKINEMIA TRAUMA/ BURNS INFECTIOUS ILLNESSES AUTOIMMUNE INFLAMMATORY DISEASES ALLERGIC INFLAMMATIONS CNS INFLAMMATIONS NONINFLAMMATORY STRESS OBESITY/VISCERAL OBESITY AGING 58 G.P. Chrousos  NHANES III (1988-1994) Metabolic Syndrome 40 35 30 Prevalence 25 20 15 10 5 0 20's 30's 40's 50's 60's 70's 80's Age (years) Park et al., 2003 Al-Attas et al. 2010  Cellular Stress Nutritional Inflammatory Oxidative  Cellular Stress Nutritional Inflammatory IR NF-kB NFAT5 Oxidative Mitochondria Keap1 (SH sensor)-Nrf2-ΑRΕ A. 24 H SAMPLING OVERNIGHT DEXAMETHASONE TEST 24 H CORTISOL PLASMA CORTISOL -D -D NS CS +D +D NS CS 8 am 8 pm DARK 8 am B. TARGET TISSUE SENSITIVITY TARGET TISSUE RESPONSE HS N R THRESHOLD FOR HARMFULNESS Chrousos JCEM 1998 CORTISOL CONCENTRATION  Results #1: Clock/Bmal1 Represses GR Transcriptional Activity through Acetylation In the Absence of In the Presence of Acetylation by CLOCK Acetylation by CLOCK Bmal1 GR Clock Acetylation A A GRE Binding A A GREs GREs GR-induced Transcriptional GR-induced Transcriptional Activity Activity NTD DBDHR LBD 1 420 480 520 777 GR K480K492K494K495 Acetylation Sites Interaction with Clock Uncoupling between Circadian Rhythm of Serum Cortisol and Tissue Glucocorticoid Sensitivity OVERNIGHT 24 H SAMPLING DEXAMETHASONE TEST Normal Stress Shift Serum Cortisol -D -D +D +D 8 am 8 pm Dark 8 am NS SS CIRCADIAN TISSUE GLUCOCORTICOID SENSITIVITY/GR ACETYLATION Functional Glucocorticoid Sensitivity GR Acetylation Glucocorticoid t Target Tissues GR Acetylation Target Tissue Hypersensitivity Target Tissue Glucocorticoid Sensitivity Pathologic Consequences 8 am 8 pm Dark 8 am THE STRESS SYSTEM AND THE METABOLIC SYNDROME Cushing Syndrome Pseudocushing Syndrome Chronic Active Alcoholism Melancholic Depression Metabolic Syndrome “Benign” Premature Adrenarche Post Long Periods of Stress Linkage Studies with GR AIDS-related insulin resistance/lipodystrophy Monkey Studies Seasonal Depression Atypical Depression  THE STRESS SYSTEM AND THE METABOLIC SYNDROME Post Long Periods of Stress Neoplasia Rx Anorexia Nervosa Malnutrition Addiction Extreme Athleticism  DEPRESSION Melancholic Atypical  cortisol  cortisol  catecholamines  catecholamines  insulin  visceral fat  lean body mass  visceral fat  bone mass Metabolic Syndrome  MUSCLE MASS Best predictor of morbidity and life expectancy  DEFINITIONS Osteosarcopenia vs. “Paradoxic”-non- Obesity vs. Overweight/Obesity Decreased bone mass: Osteopenia vs. Osteoporosis T-scores from -1 to -2.5 vs.