Research Updates: Basic Research Studies

Dr. David Van Wagoner,
Director

A fundamental area of investigation for the AFIC team is to better understand the mechanisms of atrial fibrillation in an effort to develop more effective treatments for the arrhythmia. The Basic Sciences group of AFIC, led by Dr. David Van Wagoner, has sought to evaluate the role of systemic inflammation as an important mechanism that underlies atrial fibrillation in several settings. While focused on fundamental mechanisms, the group is also seeking to directly evaluate the clinical relevance of their hypotheses through a combination of pre-clinical and clinical trials. It is hoped that these mechanistic studies will quickly lead to the implementation of rational and novel therapeutic interventions that attenuate the burden of AF, both in the state of Ohio and beyond. These studies involve important interactions both with the NIH and with a variety of companies, based in Ohio and around the country.

Inflammatory Mediators in AF: One of Dr. Van Wagoner's initial projects was to confirm a postulated link between C-reactive protein (CRP, a protein that is elevated during an inflammatory response) levels in human atrial tissue, and the occurrence of post surgical AF. The basic science group's publications resulting from this research effort have documented a selective increase in atrial CRP in patients that are in AF, suggesting that localization of the inflammatory protein reflects local tissue injury. These studies suggest that treatments that reduce CRP levels in patients may also lower the incidence of AF.

Correlation of long-term arrhythmia monitoring with inflammatory markers: A related area of interest for the basic science group is to determine whether plasma levels of any of several inflammatory biomarkers are predictive of near term occurrence of AF in patients following cardiac surgery, with the end goal of being able to prophylactically treat the symptoms, thereby preventing the onset of AF in such population. SignaLife, Inc. and Cleveland-based PrognostiX are corporate partners in this study. Studies that successfully correlate such biomarkers with the occurrence of post- operative AF would facilitate the development of a diagnostic kit for the inflammatory biomarkers that would help to determine whether therapeutic treatment to prevent AF is appropriate. A second positive outcome would be a more sensitive monitoring system for use in the perioperative period that would be designed and distributed by SignaLife.

Anti-arrhythmic and anti-inflammatory effects of omega-3 fatty acids: In parallel with the activities above, Dr. Mina Chung, Dr. Van Wagoner and Dr. Gillinov are participating in a multi-center clinical trial to investigate whether pre- and post-operative dietary supplementation with omega-3 fatty acids can decrease the incidence of post- operative AF in patients undergoing cardiac surgery. The trial is funded by Reliant Pharmaceuticals, and will begin in the fall of 2007. Dr. Van Wagoner is guiding a sub-study of this trial in which the links between systemic inflammation, atrial inflammation and the occurrence of post-op AF are directly evaluated.

Additional mechanistic studies evaluating the role of the inflammatory response following cardiac surgery are also being performed in the AFIC pre-clinical laboratory. Work on relevant animal models that directly parallels the human surgical procedures offers the opportunity to better understand 10 the dynamic aspects of the inflammatory response, and offers a platform in which it is possible to evaluate novel therapeutic approaches. The AFIC basic science group is at the forefront of such efforts.

Left atrium post LAA excision (canine model)

Lone AF genetics: Family studies have shown that offspring of a parent with AF have an increased risk for developing AF. Although it is unlikely that single gene mutations are responsible for a substantial fraction of AF cases, genetic factors clearly increase the risk of AF. AFIC is supporting the research efforts of Dr. Qing Wang and Dr. Mina Chung. Dr. Wang is using a candidate gene approach to evaluate DNA sequence variations in a variety of ion channels and proteins implicated in atrial electrical activity. Dr. Chung is pursuing studies that evaluate DNA sequence variations in the whole genome, in an effort to more broadly evaluate the genetic determinants associated with increased risk of AF. These approaches are complementary, and are sure to lead to increased understanding of the hereditable elements of AF. These studies will involve over a thousand AF patients in the next three years.

AF Research Network: Under a generous grant by the LeDucq Foundation, Dr. Van Wagoner's group and several U.S. and European collaborators are developing a trans-Atlantic atrial fibrillation research network. The principal focus of the network is to determine the molecular mechanisms that underlie calcium cycling abnormalities that act as sources of ectopic electrical activity that can initiate AF. It is reasoned that an under- standing of these mechanisms will then help to identify an additional set of targets for therapeutic intervention. The collaboration is scheduled to begin in the fall of 2007.