Following the landmark studies on scientific reproducibility, or the lack thereof, by Bayer and Amgen in the past decade, there has been a renewed interest in scientific rigor and reproducibility in both the scientific and public media. In several recent reports, the high attrition rate observed in clinical trials has been attributed to irreproducibility at the preclinical level. Cardiology is no exception to this rule. In our systematic review of the ex vivo Langendorff-perfused heart, we found methods reporting to be sparse at best, specifically as it pertains to documenting the ex vivo perfusate compositions employed in the Langendorff heart. Our lab has demonstrated that variation in perfusate compositions can unmask disease states in genetically modified animals. In this dissertation, we exploit this concept with a therapeutic end-point in mind. We show that perfusate variation, specifically sodium and calcium elevations, can attenuate conduction slowing associated with severe hyperkalemia. Likewise, elevating sodium is capable of sustaining intrinsic rhythm where hearts would otherwise go asystolic. In doing so, elevated sodium prevents repolarization prolongation in these hearts. Together, these studies would suggest that elevating extracellular sodium, and calcium, should be considered as therapeutic targets in the context of conduction defects. However, when considering the heart's primary role as a pump, we found that elevating sodium actually depresses cardiac mechanical function. This is both in a pre- and post-ischemic setting. In short, we show that electrolyte variation may influence both cardiac electrophysiology and contraction; however, an improvement in one does not guarantee an improvement in both. Maintaining proper cardiac physiological function is a complex process that is tightly regulated by the ionic makeup of the extracellular environment. To improve insights from preclinical studies at the clinical level it is paramount that researchers properly document methods so that any significant results may be properly interpreted in clinical trial design. / Doctor of Philosophy / Following the landmark studies on scientific reproducibility, or the lack thereof, by Bayer and Amgen in the past decade, there has been a renewed interest in scientific rigor and reproducibility in both the scientific and public media. In several recent reports, the high attrition rate observed in clinical trials has been attributed to irreproducibility at the preclinical level. Preclinical cardiology is no exception to this rule. In a review of the literature, we found methods reporting in a subfield (ex vivo heart preparations) of preclinical cardiology to be lackluster at best. Specifically, we found wide variation in the salt solutions used to maintain the heart's viability out of body. In our research, we show that even modest changes in salt composition will affect the outcome of preclinical research and, if methodological inconsistency is perpetuated to the clinical level, could affect the outcome of clinical trials. Importantly, this finding also reveals that small changes in salt composition may actually have a therapeutic potential that has been previously underappreciated. While we have made strides in understanding the potential for electrolyte modulation as a therapeutic option it is important to note that the clinical understanding of dynamic electrolyte changes in acute emergent situations is still poorly understood. In order to continue pursuing electrolyte modulation as a therapeutic option it will be important for us to first study and better understand the time course of systemic electrolyte changes that accompany conditions such as out-of-hospital cardiac arrest, acute myocardial infarction, shock, and hypothermia in humans.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/111481 |
| Date | 11 February 2021 |
| Creators | King, David Ryan |
| Contributors | Graduate School, Poelzing, Steven, Gourdie, Robert G., Parker, Sarah H., Grange, Robert W. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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