9/7/2012 Disclosure Upstream Therapy for Grant Atrial Fibrillation Zoll Jeffrey Olgin, MD Chief, Division of Cardiology Grant/Honorarium UC SF Medical Center Co-Director, Heart and Vascular Center Heart & Vascular Center University of California San Francisco Gilead sf San Francisco gh General Hospital San Francisco VA Medical Center CA Heart Rhythm Symposium Cardiovascular Research Institute September 2012 Gladstone Institute of Cardiovascular Disease Syllabus Common AF: An Acquired Disease • What does upstream mean? Genetic Environmental Other Diseases Aging Influences Influences (HTN, CHF, OSA, obesity) • Evidence for role of fibrosis in AF • Biology of fibrosis • EP Effects of fibrosis REMODELING • Mechanism of fibrosis in AF • Atrial selectivity of fibrosis Electrical Structural Neuro-humoral • Potential therapies Trigger Substrate ATRIAL FIBRILLATION 1
9/7/2012 AF: Current Treatment What is Does Upstream Mean? Genetic Environmental Other Diseases Genetic Environmental Other Diseases Aging Aging (HTN, CHF, OSA, obesity) (HTN, CHF, OSA, obesity) Influences Influences Influences Influences Disease Rx UPSTREAM REMODELING REMODELING Electrical Structural Neuro-humoral Electrical Structural Neuro-humoral Ablation Trigger Substrate Trigger Substrate ATRIAL ATRIAL AA Drugs FIBRILLATION FIBRILLATION ACEI/ARB/ALDOI Use to Prevent AF ACEI/ARB Use to Prevent AF Khatib, et al. Int J Cardiol 2012 Khatib, et al. Int J Cardiol 2012 2
9/7/2012 Statin Use to Prevent AF Fish Oil: Afib Recurrence after CV 4-8 week load ~7 day load Kowey, et al. JAMA 2010 Kumar, et al. Heart Rhythm 2012 Fang, et al. Br J Clin Pharm 2012 Up a Creek Without a Paddle: Exploiting Gaps in the Market Anti-arrhythmic Drugs 3
9/7/2012 Atrial Fibrillation and Fibrosis Fibrosis as Final Common Pathway Collagen IH Lone CAF Trichrome • Senescence Sirius Red Collagen IH • Mitral valve disease • HTN Sinus Rhythm • Heart Failure • Lone AF Aimé-Sempé JACC 1999 Kostin Card Res 2002 Boldt Heart 2004 Atrial Fibrillation and Fibrosis: LA Fibrosis in LA: Lone AF Lone AF Mitral Valve Disease Collagen Content (collagen/GADPH) SR LONE LONE MVD MVD MVD Parox Chronic SR Parox Chronic AF AF AF AF Marcus, et al. Heart Rhythm 2007 Boldt, et al. Heart 2004 4
9/7/2012 Heart Failure Induced Atrial TGF-ß1 Transgenic Mouse Remodeling Fibrosis AF Duration Duration (sec) CTL RAP CHF CTL RAP CHF Verheule, et al. Circulation Res 2004 Li, et al Circulation 1999 TGFß1 Mice: Cellular AF Inducibility Electrophysiology 100% 41/53 80% p < 0.001 60% % AF 40% 20% 1/48 0% Wt Tx Verheule, et al. Circ Res 2004 Verheule, et al. Circ Res 2004 5
9/7/2012 The Heart: Not Just Cardiomyocytes TGFß1 Mice: Conduction Cardiac Cell Subpopulations Myocyte Lymphocyte Endothelial Cell Fibroblast ROS Cytokines ROS Cytokines Cytokines Cytokines Verheule, et al. Circ Res 2004 Cardiac Fibroblasts Fibroblast Transformation • Fibroblast exist as small, round cells that have • Make up about 50-60% of cell types in the heart low level of collagen production – Higher in the atria • When stimulated they begin to express large quantities of actin and become factories for • Responsible for maintaining the extracellular matrix in the heart collagen and cytokines – Collagen turnover—about 5% per day – Stimulated by stretch, cytokines, injury, stress – Integrates contractile force across cardiomyocytes Fibroblast Myofibroblast – ECM conserves 3-dimensional cyto-architecture for efficient conduction and contraction • Can transform to collagen & cytokine producing Transformation “factories” called myofibroblasts • Can actively and passively exert electrical effects Ion Channels Collagen Collagen Cytokines 6
9/7/2012 Active and Passive Effects of MFb What does fibrosis do? PROPAGATION • Slows conduction (regional) • Secrete Collagen—insulator • Fibrillatory conduction/wavebreak • Larger size and coupling – Couple to CMyocyte via Connexin • Substrate for rotors – Passive conductor across MFb • Facilitates automaticity – Electrotonic interaction with Cmyocyte IMPULSE GENERATION • Collagen improves source—sink for automaticity (like sinus node) • MFb ion channel expression and coupling to Cmyocyte – Spontaneous depolarization and automaticity Isotropic Conduction Non-Uniform Anisotropy 7
9/7/2012 Conduction Heterogeneity Effects of MFb Propagation Automaticity Normal AF Substrate Rohr, Heart Rhythm 2009 Verhuele, et al AJP 2004 Mechanism of Atrial Fibrosis Catechol Heart Failure • What is the mechanism of atrial Cytokines Atrial Myocyte fibrosis? ROS Mechanical Stretch • Does preventing fibrosis prevent atrial fibrillaiton? Fibrolast TGFß Activation Collagen & ECM adapted from Burstein & Nattel, JACC 2008 8
9/7/2012 Canine Heart Failure: TGFß Human Atria: TGFß1 Levels a Atrial TGFß1 Expression AF C C AF C AF C AF AF C C C C AF C C C hTGF- β 1 β -actin b p=0.0017 p<0.0001 Relative Protein Level ( Folder Changes) Incident AF No AF All AF Lee, et al. Circulation 2006 HF Model of AF Effect of Pirfenidone Effect of Pirf on Fibrosis Conduction AF Vulnerability Lee, et al . Circulation 2006 Lee, et al. Circulation 2006 9
9/7/2012 Effect of Pirf on AF Substrate TGFß1 Expression • Why is the atria uniquely susceptible to fibrosis? Lee, et al. Circulation 2006 TGFß1 Mice: Recovery from Heart Failure Selective Atrial Fibrosis Sirius red staining (%) § § p<0.0001 A V A V t t x x W W T T , et al. Circulation 2004 Cha, et al. Circulation 2004 10
9/7/2012 Differential Fibrosis: TGFß1 Tx Mice: Differential Gene Expression Canine HF Significant difference TxA vs WtA Significant difference TxV vs WtV Log2 (TxV/WtV) MEEBO Array Atria (Wt) Atria (Tx) Ventricle Ventricle (Wt) (Tx) Log2 (TxA/WtA) Hanna, et al. Cardiovasc Res 2004 TGFß Signaling TGFß Signaling Atrial Specific — — — [Modified from Derynk] [Modified from Derynk] 11
9/7/2012 Rescue of TGFß Overexpression 35 Wt TGF Tx • Is this relevant to human atrial Wt 30 TGF Tx/NPRC KO fibrillation? 25 % FIBROSIS TGF Tx 20 15 10 TGF Tx/NPRC KO 5 0 RA LA TGFß1 Content: Human Hearts Chamber Differences in Fb Non-Failing Failing ATRIUM TGFß1 GAPDH Failing or Non-Failing TGFß1 Human Hearts Fb Culture VENTRICLE TGFß1 Atria GAPDH Cell Isolation p<0.0001 p<0.0001 Ventricle Relative Protein Level ( Fold Changes) qRT-PCR IHC p=0.6 Colagen Actin Lox Morphology ATRIUM VENTRICLE 12
9/7/2012 Isolated Human Fibroblasts: Conclusion Response to TGFß1 Collagen I mRNA � Atrial fibrosis is an important substrate for AF � TGFß1 plays a central role in animal models and Non-Failing Hearts Failing Hearts 8 human AF � The atria are uniquely susceptible to TGFß- 6 induced AF, especially in failing hearts Fold Change � Targeting fibrosis may be important target for 4 prevention and treatment of AF—a new anti- arrhythmic approach 2 0 ctrl tgfb1 ctrl tgfb1 ctrl tgfb1 ctrl tgfb1 Atrial Fb Ventricle Fb Atrial Fb Ventricle Fb Swimming Upstream Swimming Upstream 13
9/7/2012 Thank You Olgin Lab UCSF Microarray Core Emily Wilson David Erle Dolkun Rehemedula Andrea Barczak Chunhua Ding Yuanyuan Xiao Tom Everett Anges Paquet Hoa Zhang UCSF Living Heart Team Roger Chang Roger Chang George Hulley Croft Thomas Greg Marcus Jacob Vogan CTDN 54 Effect of Increasing Fibrosis Rotor Driving AF Simulated Tissue Propagation Increasing Fibrosis Heart Rhythm 2009 Jacquamet & Henriquez 14
9/7/2012 ACE Inhibition in AF: CHF Up-a-creek 700 600 Duration of AF (min) 500 400 300 200 100 0 Duration AF VTP VTP+ VTP+ Con Enal H/I Li, et al. Circulation 2001 Isolated Human Fibroblasts: Human Atria: Activated TGFß1 Response to TGFß1 LOX mRNA PAI1-Luc Activity in MLEC Assay Non-Failing Hearts Failing Hearts MLEC-PAI-Luc 4500 p=0.002 4000 Tissue 5 Luciferase Activity 3500 3000 4 Fold Change 2500 2000 3 1500 2 1000 � PAI1 500 1 0 control tgf-b1 tgf-b Ab tgf-b1+Ab non-AF non-AF+Ab AF AF+Ab 0 ctrl tgfb1 ctrl tgfb1 ctrl tgfb1 ctrl tgfb1 Atrial Fb Ventricle Fb Atrial Fb Ventricle Fb 15
9/7/2012 ACEI for AF Prevention: Meta TGFß1 Tx Mice: Analysis TGFß Signalin g WtA WtV TxA TxV TGF β RI TGF β RII Smad-2/3 pSmad-2 β -actin Healey, et al. JACC 2005 AP-1 Regulated Genes TGFß Tx Mice: Effect of TGFR Kinase Inhibition ) ) ) A ) A V A ( ( ( t ( t x t W W W T a q-RTPC – – – – ) ) ) ) V A V V § § ( ( ( ( t x x x W T T T 600 30 Collagen-I mRNA levels (% WtA) mRNA (fold difference from WtA) IL-6 PAI-1 IL-6 ET-1 PAI-1 ET-1 500 25 20 400 UC SF Medical Center 15 300 Heart & Vascular Center * * ! * * * * ! * * 10 sf 200 San Francisco gh General Hospital 5 100 San Francisco 0 VA Medical Center 0 WtA TxA TxA+Ki26894 WtV TxV TxV+Ki26894 Wt A Tx A Wt V Tx V Wt A Tx A Wt V Tx V Wt A Tx A Wt V Tx V Cardiovascular Research Institute Gladstone Institute of Cardiovascular Disease 16
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