Peter Libby Brigham & Women s Hospital Harvard Medical School
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1 Circulating and imaging biomarkers of atherosclerosis and prospects of precision management and personalized approach of cardiovascular disease Peter Libby Brigham & Women s Hospital Harvard Medical School RRM Charitable Fund Keynote Lecture 14th Global Cardiovascular Clinical Trialists Forum December 1, 2017
2 Clonal hematopoiesis: a Potent Novel Cardiovascular Risk Factor Peter Libby Brigham & Women s Hospital Harvard Medical School RRM Charitable Fund Keynote Lecture 14th Global Cardiovascular Clinical Trialists Forum December 1, 2017
3 Disclosure of financial relationships Peter Libby, MD Grant/Research support: Novartis Unpaid Consultant and/or unpaid steering or executive committee of clinical trials: Amgen, AstraZeneca, Esperion, GlaxoSmithKline, Kowa, Merck, Novartis, Pfizer Inc, Sanofi-Aventis-Regeneron Speakers Bureau: None Stock shareholder: None Scientific Advisory Board: Medimmune, DalCor, Amgen, Novartis, Corvidia, Olatec Dr. Libby declines all personal compensation from pharma or device companies
4 The Cardiovascular Continuum Dzau V, Braunwald E, & Participants. Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement. Am Heart J. 1991;121:
5 The Cardiovascular Continuum Revisited Dr.Libby Slides Libby, Nahrendorf, Swirski Leukocytes Link Local and Systemic Inflammation in Ischemic CVD JACC. 67: , 2016
6 18F-FDG Uptake Increases in Human Atheroma, Bone Marrow, and Spleen Following Acute Coronary Ischemia : The CardioSplenic Axis Emami H / Tawakol A, JACC Imaging 2015;8:121-30
7 Clonal Hematopoiesis of Indeterminate Potential (CHIP) Team Leaders Siddhartha Jaiswal Benjamin Ebert
8
9 David P. Steensma et al. Blood 2015;126:9-16 CHIP as a precursor state for hematological neoplasms by American Society of Hematology
10 We Accumulate Somatic Mutations in Blood WBC with Age Clonal Hematopoiesis of Indeterminate Potential (CHIP) Most common mutations: DNMT3A, TET2, ASXL1, and JAK2 Increase in risk: Hematologic cancer (HR 11.1) All-cause mortality (HR 1.4) Incident coronary heart disease (HR 2.0) Ischemic stroke (HR 2.6) Colored bands, in increasingly lighter shades, represent the 50th, 75th, and 95th percentiles. Jaiswal...Ebert N Engl J Med 2014;371: DOI: /NEJMoa
11 CHIP as a precursor state for hematological neoplasms. David P. Steensma et al. Blood 2015;126:9-16
12 Cancer deaths account for a only a small proportion of the increased mortality in individuals with clonal hematopoiesis Development of Hematologic Cancers ~5%/10 yr Effect of Somatic Mutations on All-Cause Mortality (CHIP) ~50%/10 yr Jaiswal S et al. N Engl J Med 2014;371:
13 Could Atherosclerotic Cardiovascular Disease Account for the Mortality Gap in Clonal Hematopoiesis? Can we demonstrate worsened cardiovascular outcomes in CHIP? Is CHIP causal in atherosclerotic cardiovascular disease (CVD)? What mechanisms could explain an increase in CVD due to CHIP?
14 June 21, 2017, at NEJM.org. DOI: /NEJMoa
15 Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease We used whole-exome sequencing to detect the presence of CHIP in peripheralblood cells and associated such presence with coronary heart disease using samples from four case control studies that together enrolled 4794 carriers of CHIP and 3537 controls. Jaiswal et al., June 21, 2017, at NEJM.org. DOI: /NEJMoa
16 Cohorts Studied BioImage: multi-ethnic, observational study 6,699 US adults Malmo Diet and Cancer (MDC) Study of ~30,000 ATVB: case-control study of early-onset MI in 125 Italian CCUs Pakistan Risk for Myocardial Infarction Study (PROMIS) case-control study of MI
17 CHIP associates with coronary heart disease (CHD) in two prospective cohorts Sekar Kathiresan Cox proportional hazards models which included age, sex, diabetes status, total cholesterol, HDL cholesterol, hypertension, and smoking history as covariates Jaiswal et al., NEJM 2017
18 The magnitude of independent risk associated hypertension, cholesterol, or inflammation Risk Ratio (95%CI) hscrp Systolic BP Total cholesterol Non-HDLC 1.37 ( ) 1.35 ( ) 1.16 ( ) 1.28 ( ) Risk Ratio (95%CI) per 1-SD higher usual values Adjusted for age, gender, smoking, diabetes, BMI, triglycerides, alcohol, lipid levels, and hscrp Emerging Risk Factor Collaborators, Lancet January 2010 CR-19
19 Clonal hematopoiesis of indeterminate potential (CHIP) associates with early-onset myocardial infarction (MI) Jaiswal et al., NEJM 2017 Cox proportional hazards models which included age, sex, and diabetes status as covariates
20 Number Mutation spectrum of human clonal hematopoiesis Associated with coronary heart disease Mutant mouse available
21 Why does atherosclerotic cardiovascular disease associate with clonal hematopoiesis of indeterminate potential (CHIP?) Two possibilities: 1) CHIP accompanies aging, and has no causal association with cardiovascular disease 2) CHIP causes cardiovascular disease
22 Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice José J. Fuster, Susan MacLauchlan, María A. Zuriaga, Maya N. Polackal, Allison C. Ostriker, Raja Chakraborty, Chia-Ling Wu, Soichi Sano, Sujatha Muralidharan, Cristina Rius, Jacqueline Vuong, Sophia Jacob, Varsha Muralidhar, Avril A. B. Robertson, Matthew A. Cooper, Vicente Andrés, Karen K. Hirschi, Kathleen A. Martin, and Kenneth Walsh Published by AAAS Science Volume 355(6327): February 24, 2017
23 Tet2 loss of function augments experimental atherosclerosis 8-12 week old 8 week old Vav1-Cre, Tet2 fl/fl Vav1-Cre, Tet2 fl/+ Vav1-Cre, Tet2 +/+ Bone marrow transplantation Ldlr-/- female 4 weeks 5 weeks 9 weeks 13 weeks 17 weeks Diet: 1.25% cholesterol Method: Maganto-Garcia, E., Tarrio, M. and Lichtman, A Current Protocols in Immunology. 96:15.24: Jaiswal et al., NEJM 2017
24 Transfer of Tet2-deficient marrow increases lesion size in the mouse aortic root WT KO From ccf.org 2.0-fold larger 1.7-fold larger 1.3-fold larger Jaiswal et al., NEJM 2017
25 Mice receiving Tet2-deficient marrow develop larger lesions in the descending aorta Maganto-Garcia, E., Tarrio, M. and Lichtman, A Current Protocols in Immunology. 96:15.24: weeks Jaiswal et al., NEJM 2017
26 Tet2 deficiency does not alter serum lipid levels in ApoE -/- mice Tet2 -/- ; Vav1-Cre Tet2 +/+ ; Vav1-Cre Total cholesterol (mg/dl) 1131 ± ± 230 HDL cholesterol (mg/dl) 111 ± ± 16 LDL cholesterol (mg/dl) 923 ± ± 227 Triglycerides (mg/dl) 486 ± ± 126 Fasting serum lipids after 17 weeks on high cholesterol diet LDL-C level calculated from Friedewald formula Jaiswal et al., NEJM 2017
27 Tet2 deficiency does not alter blood cell indices in ApoE -/- mice White blood cell count (K/uL) Tet2 -/- ; Vav1-Cre Tet2 +/+ ; Vav1-Cre 8.2 ± ± 2.9 Hemoglobin (mg/dl) 13.4 ± ± 2.4 Hematocrit (%) 49.1 ± ± 8.6 Platelets (K/uL) 696 ± ± 194 Complete blood count after 5 weeks on high cholesterol diet Jaiswal et al., NEJM 2017
28 Myeloid-specific loss of Tet2 suffices to accelerate atherosclerosis Lymphoid progenitors Vav1-Cre T-Cell B-Cell Aortic root 10 weeks Lyz2-Cre Monocyte Hematopoietic stem cell Neutrophil p=0.003 Myeloid progenitors Megakaryocyte 1.7-fold larger Erythrocyte Jaiswal et al., NEJM 2017
29 Gene expression analysis on bone marrowderived macrophages exposed to LDL Vav1-Cre,Tet2 fl/fl Vav1-Cre,Tet2 +/+ Culture bone marrow derived macrophages with M-CSF Incubate with vehicle or LDL cholesterol for 24h RNA-seq Jaiswal et al., NEJM 2017
30 Tet2-deficient macrophages overexpress inflammatory chemokines and cytokines in response to LDL Genotype LDL Jaiswal et al., NEJM 2017
31 Tet2-deficient macrophages overexpress IL-1 beta and IL-6 mrna in response to LDL
32 Tet2-deficiency also increases circulating CXC chemokine concentrations in vivo p=0.08 p=0.05 p=0.08 p=0.05 p= p=0.02 p= p=0.02 p=0.001 p=0.07 p=0.001 p=0.22 p=0.02 p=0.11 p=0.03 p=0.02 p=0.11 p=0.07 p=0.22 p=0.03 Transplanted mice after 17 weeks on high-cholesterol diet Jaiswal et al., NEJM 2017
33 Tet2 deficiency likely enhances monocyte recruitment Cxcr1 Cxcr2 Arterial intima Cxcl1 Cxcl2 Cxcl3 Cxcl1 Cxcl2 Cxcl3 Modified from Libby P. Inflammation in atherosclerosis. Nature 2002;420:
34 Clonal hematopoiesis & atherosclerotic events Clonal hematopoiesis increases with age Those with clonal hematopoiesis have much greater risk of cardiovascular events than of developing hematologic malignancy
35 Clonal hematopoiesis & atheroslcerotic events The cardiovascular risk associated with clonal hematopoiesis is independent of and that of traditional risk factors (save for age) Mouse studies support causality of clonal hematopoiesis in ASCVD
36 The Mortality Gap in Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease: The Missing Links Can we demonstrate worsened cardiovascular outcomes in CHIP? Is CHIP causal in atherosclerotic cardiovascular disease (CVD)? What mechanisms could explain an increase in CVD due to CHIP?
37 TET enzymes have demethylase activity TET1 TET2 TET3 TET catalyzed reactions are the primary mechanism of demethylation of cytosine, but the oxidized intermediates may also have decarboxylase. biological functions Ito et al., Science 2011 Figure S1. Chemistry involved in the thymine to uracil conversion in the thymidine salvage pathway and a proposed mechanism for 5mC demethylation Thymine-DNA (A) Part of the thymidine salvage pathway. Thymine (T) is converted glycosylase to 5- hydroxymethyl U (5hmU), 5-formyl U (5fU), and iso-orotate by thymine hydroxylase (THase) in three consecutive oxidation reactions, each requiring O 2,! -KG while releasing CO 2 and succinate. Iso-orotate is then converted to uracil by i so-orotate decarboxylase. (B) Proposed mechanism of oxidative DNA demethylation initiated by Tet proteins. Similar to THase, Tet proteins can potentially oxidize 5mC to produce 5- hydroxymethyl C (5hmC), 5- formyl C (5fC), and 5-carboxyl C (5caC), which then may be converted to C by a He et al., Science 2011 Fig. S14. $ %&' (!)%*!+, -!&'. ' /01(2/3%4!5*%. %/' &!61!7' /!24&!7+ 8 9!: %4;' <=/3>'!01&*%?1(
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39 Thanks! Siddhartha Jaiswal Benjamin Ebert Eugenia Schvarz Galina Sukhova RRM Charitable Fund
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