Title: Basis of Novel Therapeutic approaches for Cardiovascular Disease

Abstract:

Statement of the Problem: Cardiovascular Disease remains the major killer in the Western world despite the demonstrated benefits of lipid lowering therapies. Novel approaches are being investigated to address further therapeutic needs, currently with limited success. Processes leading to heart attacks include lipid deposition (i.e. cholesterol), lesion progression and recruitment of immune cells with their activation, subsequent plaque rupture and release of prothrombotic components. Ultimately, blockage of blood flow occurs. Of the pathways involved, two major mechanistic pathways have been under study: 1). elevation of HDL, by any means, to enhance cholesterol efflux and removal of cholesterol from the vascular wall to drive the process of reverse cholesterol transport (RCT). This is movement of cholesterol from cells of the atherosclerotic vasculature to HDL in the blood and subsequently to the liver for modification and excretion to the gut for elimination from the body, and 2). regulation of inflammatory pathways in attempts to inhibit vessel wall plaque degradation and rupture leading to heart attacks.
Epidemiologic studies have shown significant correlations of HDLc levels with reduced cardiovascular events. A number of methods for elevating HDL have been under study, among which a significant focus has been to inhibit the activity of cholesterol ester transfer protein (CETP). CETP is an enzyme that transfers cholesterol ester from HDL to LDL. Blocking this enzyme leads to elevations of HDL cholesterol and increases in HDL particle size. Though this approach has successfully enhanced cellular cholesterol efflux, the first step in RCT, numerous attempts in the clinic have failed to show benefit in reducing cardiovascular events. Recent findings have suggested that subsequent function of the HDL particles may be affected in a negative way, with activities of HDL modifying enzymes reduced as well as uptake by hepatic cells. Thus, although initially seemingly successful in enhancing efflux, cardiovascular events were not reduced. A number of additional / novel approaches to HDL modulation are now under study.
A second approach currently under investigation is regulation of clinical events through inhibition of inflammation in the vascular wall. With the initiation of atherosclerosis, lipid is deposited and immune cells including macrophages are recruited to the site. As lesions develop, cells become engorged with lipid, becoming foam cells, and through during these processes, become activated. Activation enhances cell recruitment and release of cytokines and expression of adhesion molecules. Proteolytic enzymes are also released, with breakdown of the intimal surface and of vulnerable regions of the lesion cap, resulting rupturing of the plaque. Pro-thrombotic contents of the vessel wall are then released, leading to blockage of the lumen of the vessel, and of blood flow. Inhibition of immune cell recruitment and activation are an important approach to therapeutic treatment of cardiovascular disease, with some success established, but significant improvements to the approaches needed. Innovative methods to effect this process will be discussed.
Conclusion: Several novel therapeutic approaches to treatment of cardiovascular disease are under study, but improvements to achieve therapeutic benefit will be required.

Biography:

Steven J. Adelman, Founder and CEO of Vascular Strategies LLC, and CSO, NanoPhagix LLC has more than 25 years’ experience in drug discovery and development. Previously led several initiatives at Wyeth Pharmaceuticals: Senior Director, Cardiovascular and Metabolic Disease Research and Senior Director, Atherosclerosis CV/Women’s Health. Activities included identifying and validating discovery and development programs (small molecules and biologics), advancing more than 10 compounds through IND into clinical development. Expertise includes atherosclerosis and CVD, inflammation, immune biology, and women’s health. Worked extensively on rapamycin (sirolimus, Rapamune) for transplant indications and subsequent incorporation on the Cypher-stent, first successful drug-eluting coronary stent. Honors and memberships include elected Fellow American Heart Association; Golden Heart Member, Council on Arteriosclerosis, Thrombosis and Vascular Biology, Basic Sciences Council, Functional Genomics and Translational Biology Interdisciplinary Working Group, AHA, and International Atherosclerosis Society. Authored more than 100 articles and abstracts and holds over 30 patents.