Coronary heart disease is the leading cause of death worldwide. In 2001 there were 2 million CHD hospitalizations with an annual cost of $133 billion. Current strategies for the treatment of acute coronary syndromes, which includes restoring epicardial coronary artery patency, do not consistently restore microvascular perfusion, which has adverse clinical consequences. Drag-reducing polymers (DRPs) may fill this void. DRPs reduce vascular resistance, potentially by targeting the rheology and hydrodynamics of blood flow. Under AHA support, the Principal Investigator has studied the effects of DRPs on myocardial perfusion in the setting of graded canine coronary stenoses. He has found that minute intravascular concentrations of DRPs normalize myocardial perfusion and improve coronary flow reserve by decreasing capillary resistance, and this may provide a novel approach for the treatment of coronary heart disease. Traditionally, DRPs are known to augment pipe flow through reductions in fluid resistance. In vascular systems, similar mechanisms are theorized but the precise microvascular mechanism of action is unknown. Having established the potential health benefits of DRPs in experimental animal models, further clinical development as a therapeutic strategy will require a greater understanding of its microvascular mechanisms. Accordingly, this research program builds on the Pi's intact animal data by investigating DRPs effects at the microcirculatory level. The Principal Investigator will learn sophisticated tools for intravital microcirculation research, including measurements of microvascular pressure, microvascular hematocrit, and red cell and leukocyte kinetics. These techniques will be used to determine whether DRPs enhance perfusion through (1) Alterations in hydrodynamics by increasing precapillary driving pressure;(2) Changing microvascular red cell distribution;(3) Altering leukocyte-endothelial interactions;or a combination thereof. The Principal Investigator's short term goal is to gain a fund of knowledge in the field of the microcirculation and to learn the techniques to answer the questions posed by this proposal. He will then apply his new skill set to address questions in his field of clinical expertise, interventional cardiology. His ultimate goal is to improve treatments aimed at the coronary microcirculation, including treatment of coronary 'no-reflow,'by delving into its microvascular mechanisms. By interrogating the microvascular mechanisms of DRPs, this proposal provides a vehicle to learn these methodologies.
|Brands, Judith; Kliner, Dustin; Lipowsky, Herbert H et al. (2013) New insights into the microvascular mechanisms of drag reducing polymers: effect on the cell-free layer. PLoS One 8:e77252|
|Pacella, John J; Kameneva, Marina V; Brands, Judith et al. (2012) Modulation of pre-capillary arteriolar pressure with drag-reducing polymers: a novel method for enhancing microvascular perfusion. Microcirculation 19:580-5|