Research Background on Atherosclerosis and Inflammatory Biomarkers:
Coronary artery disease remains the number one cause of death and in a major cause of morbidity among men and women in the United States.
Traditional risk factors for CAD include age, hypertension, smoking, diabetes, elevated total cholesterol and decreased HDL. However approximately 20% of cardiac events will occur in the absence of any of these risk factors. Additionally, half of these events will occur in the absence of any lipid abnormalities. Thus, existing biomarkers and risk stratification guidelines could be better in predicting cardiovascular risk.
In vitro, HDL is thought to mediate the transport of excess cholesterol from the periphery (including the arterial wall) to the liver and promotes efflux of cholesterol from foam cells in atherosclerotic lesions (reverse cholesterol transport).
Despite HDL's inherent function as a cholesterol scavenger and transporter, it remains an open question as to whether or not low HDL levels are a causal risk factor for CHD, or if HDL may be used as a treatment target. It is difficult to draw results data derived from HDL drug and lifestyle intervention studies, because these studies tend to affect other risk factors such as lipid components, and especially triglycerides. Observational studies have shown that low HDL is associated with an increased risk for CAD, however in the high HDL group there is not always a reduced risk.
It is now understood that atherosclerosis is fundamentally an inflammatory disorder and both lipids and inflammation need to be addressed simultaneously in order to more accurately predict cardiovascular risk. It is now known that some of the clinical benefits of HMG-CoA reductase inhibitors (statins) and angiotensin-converting enzyme inhibitor therapy may derive from interrupting pro-inflammatory pathways. With regards to atherosclerosis, the only biomarker we have data available for is hsCRP. Research is ongoing for other inflammatory biomarkers.
Neuroendocrine Signaling and Obesity/ Weight Loss Research:
The association between obesity and CAD is well established, with weight reduction being one of the most important goals in the treatment of atherosclerosis. The current epidemiological trend is producing obesity at unprecedented rates and obesity and obesity- associated free radical production are emerging as the most important contributors to increased cardiovascular morbidity and mortality. Currently available pharmaceuticals either alone or in combination have been shown to be only modestly effective in treating weight loss, and even less effective for treating weight maintenance following weight loss, which demonstrates that the causes of obesity are not completely understood. Considerable research is currently underway in both the causative and curative aspects of obesity with respects to fat absorption, appetite suppression, inflammation, lifestyle intervention and dieting in conjunction with neuroendocrine signaling and protein signaling, in order to provide the best palliation, treatment, care and prevention of obesity.
Basic Science and Drug Development:
Prof. David Gortler's basic science research explores various cell signaling pathways as related to heart disease, vascular wall thickening, intimal hyperplasia, and vascular inflammation. The constellation of inflammatory markers examined include (TNF-alpha, INOS, IL-6, IL1b,COX-2, LOX, PGE-2, MCP-1, Osteopontin (IL-17), INOS, IL-6, IL1b, MCP-3, MMP9, TF, M-CSF, and VCAM-1) Closely related studies also includes the non-random localization of atherosclerotic plaques in the coronary vasculature. Considerable evidence suggests that impaired endogenous atheroprotective mechanisms occur at branch points in arteries, where the endothelial cells experience cyclic strain and shear stress. Pathways examined include the signaling cascade along PI 3-kinase (akt/PKB, BAD, nf-Kb, others) and their roles in hemodynamic stimuli as related to intimal hyperplasia, and atheroma formation mediated through apoptotic pathways.
His clinical research involves the early- and late-phase review and development of novel compounds which have the potential to modulate lipid production, atheroprogression, vascular inflammation, HDL modulation, hsCRP, weight loss, neuroendocrine signaling and related areas of metabolism and endocrinology.