Pharmacologic Stabilization of Vulnerable Plaque: A Premature

Concept?

LDL

Ox LDL

Infection/inflammation

Homocysteine

Smoking

Endothelial release of MCP-1NO

PGI2

HSPG

tPA

Tm

ICAM 1

VCAM 1

TSP

TNF α

IL 1

PAI1

MONOCYTE:

Chemo-attraction (MCP 1)

Attachment(LFA1, Mac1,etc)

Attraction (NFκB)

Proliferation (TNF α,MCSF)

Secretion of TNF α , IL-1, MCP-1, NO

T cell activation (CD 40)

Inhibition of SMC metabolism Activation of MMPs

Apoptosis of SMC Activation of acid proteases

Angiogenesis

Diet low in antioxidants

Low HDL

A-II

Inflammation Coagulation

Pharmacologic Stabilization of Vulnerable Plaque

Anti-inflammatory agents (aspirin, Plavix, etc) Antiplatelets Anticoagulants Antiplatelets Anti-microbials Lipid-lowering agents Antioxidants Beta blockers Angiogenesis inhibitors (endostatin, α VEGF) eNOS inductors

Pharmacologic Stabilization of Vulnerable Plaque, contd.

ACE inhibitors MMP inhibitors Vasodilators (amlodipine, TNG) Apo A1 Milano, HDL TF inhibitors CETP inhibitors Cytokines antagonists (selectins, ICAM, VCAM, NFκB, TGF-

ß, MCP-1, TNF-α, PDGF) Retinoids (retinoic acid, TGF-ß) Antibodies to CD40 ligand Cap strengthening (TGF -ß, antibody to IF γ)

Anti-inflammatory

AspirinNSAIDsCox-2 inhibitorsStatins

Triggers of Plaque RuptureAwakening Rx: AspirinExercise Anti-adrenergicsAnger Timing of Rx Fear (e.g., earthquake) CounselingSexual activity Sedatives?Fatty meal Anti- depressants? Cocaine, decongestants, marijuanaCold weatherPollutionMondays

Statins

SimvastatinAtorvastatinPravastatinFluvastatinLovastatinCerivastatinRosuvastatin

Anti-microbials

roxithromycin

azithromycingancicloviroseltamivirzanamivir

Future

Antioxidants α-tocopherol β-carotene Vitamin C Selenium Flavunoids Green tea N-acetyl cycteine Probucol Dietary fat reduction eNOS induction Statins

Antiplatelets and Antithrombotics

Aspirin, Ticlopidine, ClopidogrelHeparin, LMWHGPIIb/IIIa inhibitors

Antibodies (Abciximab)Synthetic antagonists (Eptifibatide, Tirofiban)

Thrombin Inhibitors (Argatroban,Hirudins)

                                                                                                                                                                      

                                    

Texas Heart Institute University of Texas-Houston

Center for Vulnerable Plaque Research