Basic Mechanisms of Atherosclerosis and Plaque Rupture: Clinical Implications

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1 12 th Annual Cardiovascular Disease Prevention Symposium February 8, 2013 KEYNOTE ADDRESS Basic Mechanisms of Atherosclerosis and Plaque Rupture: Clinical Implications Ira Tabas, M.D., Ph.D. Richard J. Stock Professor of Medicine, Cell Biology, and Physiology 12 th Annual Cardiovascular Disease Prevention Symposium February 8, 2013 KEYNOTE ADDRESS Basic Mechanisms of Atherosclerosis and Plaque Rupture: Clinical Implications No Conflicts of Interest to Disclose Acute Coronary Syndrome: The Culprit Thrombus Necrotic atherosclerotic lesion

2 Progression of Atherothrombotic Vascular Events Years; common; asymptomatic Moore & Tabas, Cell 2011 Progression of Atherothrombotic Vascular Events Years; common; asymptomatic rare; acute vascular events Moore & Tabas, Cell 2011 Basic Mechanisms of Atherosclerosis and Plaque Rupture Mechanisms of atherogenesis Overview Clinical implications Advanced plaque progression The maladaptive inflammatory response: defective inflammation resolution Summary and conclusions

3 Tabas et al., Circulation, 2007 Joy Frank Tabas et al., Circulation, 2007 Tabas et al., Circulation, 2007

4 Tabas et al., Circulation, 2007 The Macrophage Foam Cell R. Gerrity Defective inflammation resolution due to persistent LP retention Amplified LP retention Plaque necrosis mature DC Tabas et al., Circulation, 2007

Amplified LP retention Plaque necrosis mature DC Tabas et al.

Plaque Rupture Mechanisms of atherogenesis Overview Clinical

inflammatory response: defective inflammation resolution

apob-lps should decrease heart disease The fallacy of terms

5 Amplified LP retention Plaque necrosis mature DC Tabas et al., Circulation, 2007 Basic Mechanisms of Atherosclerosis and Plaque Rupture Mechanisms of atherogenesis Overview Clinical implications Advanced plaque progression The maladaptive inflammatory response: defective inflammation resolution Summary and conclusions Clinical Predictions Lowering apob-lps should decrease heart disease The fallacy of terms like "low" or "healthy" levels of plasma LDL Lower is better Earlier is better

6 Atherogenesis "High" levels of apob-lipoproteins in the bloodstream + A "susceptible" arterial wall (i.e., susceptible to apob-lp retention or responses to retention) Therapeutic Approach to Prevent and Reverse Atherosclerosis "High" levels of ApoB-lipoproteins in the bloodstream Probability of ApoB-LP entry and then retention in the subendothelium Lowering Plasma LDL Decreases Coronary Artery Disease % with CAD event CARE HPS HPS AFCAPS S LIPID LDL-C (mg/dl) WOSCOPS Secondary prevention trials Primary prevention trials Adapted from Illingworth. Med Clin North Am. 2000;84:23. At:

Clinical Predictions Lowering apob-lps should decrease heart disease The fallacy of terms like "low" or "healthy" levels of plasma LDL Lower is better Earlier is better

7 Clinical Predictions Lowering apob-lps should decrease heart disease The fallacy of terms like "low" or "healthy" levels of plasma LDL Lower is better Earlier is better Clinical Predictions Lowering apob-lps should decrease heart disease The fallacy of terms like "low" or "healthy" levels of plasma LDL Lower is better Earlier is better

Lower is Better and "Safe" Hunter-gatherer societies (and other mammals) Cord blood Familial hypobetalipoproteinemia "Zero-risk" extrapolation of LDL-lowering trials LDL-lowering trial subgroups

8 Lower is Better and "Safe" Hunter-gatherer societies (and other mammals) Cord blood Familial hypobetalipoproteinemia "Zero-risk" extrapolation of LDL-lowering trials LDL-lowering trial subgroups (PROVE-IT, JUPITER) LDL receptor is 50% saturated at 10 mg/dl Clinical Predictions Lowering apob-lps should decrease heart disease The fallacy of terms like "low" or "healthy" levels of plasma LDL Lower is better Earlier is better

9 Earlier is Better Genetic syndromes that lower LDL at birth (PCSK9) Clinical studies where intervention is early vs. late Basic Mechanisms of Atherosclerosis and Plaque Rupture Mechanisms of atherogenesis Overview Clinical implications Advanced plaque progression The maladaptive inflammatory response: defective inflammation resolution Summary and conclusions Acute Atherothrombosis The Trigger for Acute Coronary Syndromes YEARS YEARS MINUTES Abrams (2005) NEJM 352:2524

Common Cause of Cardiac Events Thin fibrous cap Necrotic core Inflammatory milieu

10 The Plaque Rupture Theory of Acute Atherothrombosis necrotic core Plaque Morphology is More Important than Plaque Size Mild-to-Moderate Lesions that Rupture are the Most Common Cause of Cardiac Events Thin fibrous cap Necrotic core Inflammatory milieu Plaque Rupture Thrombus Ruptured plaque at area of thinned fibrous cap Necrotic Core Constantinides

11 The Problem? 2-3% "Benign" atherosclerotic lesion Ruptured "vulnerable" plaque heart attack sudden cardiac death unstable angina stroke The Necrotic Core An Essential Feature of Vulnerable Plaques Necrotic Core inflammation coagulation thrombosis proteases stress on fibrous cap How Does the Necrotic Core Form? Necrotic Core "graveyard of dead Mφs"

12 What is the link between Mφ death and necrotic core formation? Necrotic Core "graveyard of dead Mφs" Mφ Death in Atherosclerosis Tabas ATVB Nov 2005 Mφ Death in Atherosclerosis Tabas ATVB Nov 2005

13 Other Processes in Plaque Instability apoptotic SMCs cytokines, proteases pro-coagulants primary necrosis (RIP1/3) living Mφs, DCs, T cells, mast cells, neutrophils Defective Efferocytosis Efferocytosis Safe disposal of apoptotic cells Anti-inflammatory signaling, including TGFβ

14 Efferocytosis C1q TG-2 Tim-1 Tim-4 Mertk Efferocytosis C1q TG-2 Tim-1 Tim-4 Mertk Pathologically defective efferocytosis in advanced atheromata apoptotic Mφ induces inflammation X X Post-apoptotic necrosis efferocytic Mφ Thorp & Tabas 2009 J Leuk Biol

15 Pathologically defective efferocytosis in advanced atheromata L N defective + = efferocytosis presence of apoptotic cells (TUNEL) tissue necrosis (collection of post-apoptotic cells) Pathologically defective efferocytosis in advanced atheromata Arterioscler Thromb Vasc Biol. 2005;25: Phagocytosis of Apoptotic Cells by Macrophages Is Impaired in Atherosclerosis Dorien M. Schrijvers, Guido R.Y. De Meyer, Mark M. Kockx, Arnold G. Herman, Wim Martinet Pathologically defective efferocytosis in advanced atheromata Arterioscler Thromb Vasc Biol. 2005;25: Phagocytosis of Apoptotic Cells by Macrophages Is Impaired in Atherosclerosis Dorien M. Schrijvers, Guido R.Y. De Meyer, Mark M. Kockx, Arnold G. Herman, Wim Martinet WHAT IS THE MECHANISM?

16 Basic Mechanisms of Atherosclerosis and Plaque Rupture Mechanisms of atherogenesis Overview Clinical implications Advanced plaque progression The maladaptive inflammatory response: defective inflammation resolution Summary and conclusions DEFECTIVE INFLAMMATION RESOLUTION persistent amplified LP retention LP retention tissue damage (DAMPs) Plaque necrosis mature DC Tabas et al., Circulation, 2007 Non-resolving Inflammation Tabas & Glass Science 2013

17 Atherosclerosis ApoB LP retention Persistent and amplified apob LP retention Tabas & Glass Science 2013 Hallmarks of Defective Inflammation Resolution in Atherosclerosis persistent monocyte influx persistent DAMPS (apob LPs) thinning of fibrous cap oxidative stress persistent inflammation defective efferocytosis necrosis additional DAMPS defective Mφ egress adapted from Tabas Nature Rev. Immunol 2010 Therapeutic Opportunities in Atherosclerosis? persistent monocyte influx persistent DAMPS (apob LPs) thinning of fibrous cap oxidative stress persistent inflammation defective efferocytosis necrosis additional DAMPS defective Mφ egress

18 Therapeutic Opportunities in Atherosclerosis? persistent monocyte influx persistent DAMPS (apob LPs) lower apob lipoproteins or block retention thinning of fibrous cap oxidative stress persistent inflammation defective efferocytosis necrosis additional DAMPS defective Mφ egress Therapeutic Opportunities in Atherosclerosis? thinning of fibrous cap oxidative stress persistent inflammation defective efferocytosis necrosis additional DAMPS persistent monocyte influx dampen inflammation and restore homeostasis persistent DAMPS (apob LPs) monocyte influx efferocytosis fibrous cap oxidative stress defective Mφ egress Therapeutic Opportunities in Atherosclerosis? thinning of fibrous cap oxidative stress persistent inflammation defective efferocytosis necrosis additional DAMPS boost natural regulatory mechanisms persistent (e.g., Tregs) monocyte influx dampen inflammation and restore homeostasis persistent DAMPS (apob LPs) monocyte influx efferocytosis fibrous cap oxidative stress defective Mφ egress

19 Examples of Treg-mediated strategies that reduce atherosclerosis in mice "Vaccination" with HSP60/65, oxldl, apob, β2-gp Inject tolerogenic DCs: pre-treat with IL-10 or rapamycin, then pulse with above antigens Therapeutic Opportunities in Atherosclerosis? thinning of fibrous cap oxidative stress persistent inflammation defective efferocytosis necrosis additional DAMPS administer exogenous mediators persistent of resolution monocyte influx dampen inflammation and restore homeostasis persistent DAMPS (apob LPs) monocyte influx efferocytosis fibrous cap oxidative stress defective Mφ egress

20 Nature's Solution to the Challenge of Host Defense Tissue damage DAMP Tissue damage DAMP Specialized proresolving mediators (SPMs) Tabas & Glass Science 2013 Can RvD1 improve atherosclerosis? Resolvin D1 (RvD1) ALX receptor RESOLUTION OF INFLAMMATION RvD1 Treatment of Fat-Fed Ldlr -/- Mice Lowers the Extent of Advanced Atherosclerosis Veh AT-RvD1, n2 Fredman, unpublished data

Nanoparticle-mediated drug delivery to areas of arterial "injury" Karmaly, Fredman, et

21 Can another type of ALX agonist improve atherosclerosis? Annexin A1 (Ac2-26) Resolvin D1 (RvD1) ALX receptor RESOLUTION OF INFLAMMATION Nanoparticle-mediated drug delivery to areas of arterial "injury" Karmaly, Fredman, et al., PNAS 2013 Ac2-26 NP Treatment of Fat-Fed Ldlr -/- Mice Suppresses Advanced Plaque Development scrambled peptide NPs Ac2-26 NPs

Basic Mechanisms of Atherosclerosis and Plaque Rupture Mechanisms of atherogenesis Overview Clinical implications Advanced plaque progression The maladaptive inflammatory response: defective

22 Basic Mechanisms of Atherosclerosis and Plaque Rupture Mechanisms of atherogenesis Overview Clinical implications Advanced plaque progression The maladaptive inflammatory response: defective inflammation resolution Summary and conclusions Atherosclerosis Plaque necrosis Defective Inflammation Resolution persistent monocyte influx persistent DAMPS (apob LPs) thinning of fibrous cap oxidative stress persistent inflammation defective efferocytosis necrosis additional DAMPS defective Mφ egress

Therapeutic Opportunities lower apob lipoproteins or block retention persistent monocyte influx boost natural regulatory mechanisms (vaccines) or

efferocytosis necrosis additional DAMPS defective Mφ egress WHY? Antagonistic Pleiotropy G. C.

23 Therapeutic Opportunities lower apob lipoproteins or block retention persistent monocyte influx boost natural regulatory mechanisms (vaccines) or administer mediators of inflammation resolution persistent DAMPS (apob LPs) thinning of fibrous cap oxidative stress persistent inflammation defective efferocytosis necrosis additional DAMPS defective Mφ egress WHY? Antagonistic Pleiotropy G. C. Williams, Evolution, 1957 Aging and aging-related diseases evolve because natural selection favors genes that confer benefits early in life, even though those genes may prove detrimental to an organism later in life.

24 Atherosclerosis as Example of Antagonistic Pleiotropy inflammation calcification persistent stimulus (apob LPs) non-resolving thrombosis Atherosclerosis as Example of Antagonistic Pleiotropy persistent stimulus (apob LPs) non-resolving inflammation calcification thrombosis fights infection and promotes resolution heals broken bones prevents bleeding Atherosclerosis as Example of Antagonistic Pleiotropy persistent stimulus (apob LPs) non-resolving inflammation calcification thrombosis fights infection and promotes resolution heals broken bones prevents bleeding transient stimulus resolving

25 Atherosclerosis as Example of Antagonistic Pleiotropy inflammation calcification fights infection and promotes resolution heals broken bones persistent stimulus (apob LPs) non-resolving thrombosis } kills you later in life prevents bleeding } keeps you alive to pass on the gene pool transient stimulus resolving Getting Caught in the Therapeutic Window inflammation calcification fights infection and promotes resolution heals broken bones persistent stimulus (apob LPs) non-resolving thrombosis } kills you later in life prevents bleeding } keeps you alive to pass on the gene pool transient stimulus resolving Anti-inflammatory strategies A Possible Opening of the Therapeutic Window inflammation calcification fights infection and promotes resolution heals broken bones persistent stimulus (apob LPs) non-resolving thrombosis } kills you later in life prevents bleeding } keeps you alive to pass on the gene pool transient stimulus resolving Inflammation resolution strategies

Atherosclerosis is an Inflammatory Disease: Does it Matter? Atherosclerosis is an Inflammatory Disease: Does it Matter?

12 th Annual Cardiovascular Disease Prevention Symposium February 8, 2013 Atherosclerosis is an Inflammatory Disease: Does it Matter? Ira Tabas, M.D., Ph.D. Richard J. Stock Professor of Medicine, Cell