Parametric evaluation of the effect of aortic regurgitation on ventricular performance

Abstract

Aortic regurgitation (AR) refers to the backflow of blood from the aorta into the left ventricle (LV). AR is an important clinical problem with an incidence of approximately 10% in the United States. Within 10 years from diagnosis, approximately 78% of AR patients either undergo surgery or mortality. The clinical diagnosis (standard of care) of the severity of AR (mild, moderate, and severe) currently relies on several echocardiography-based measurements; however, over time, AR also induces ventricular remodeling resulting from increased pressure and volume overload. Although the survival of patients in the early stages of AR (usually mild to moderate) is relatively high after a 10-year period, at the onset of LV function failure, patient survival rapidly drops. It has therefore become a necessity to optimize the timing of surgical intervention for patients with AR. To this end, several research studies have proposed various metrics to more accurately stratify AR than the current standard of care methods. However, the proposed metrics still focus on the functionality of the aortic valve alone and fail to take into account LV functionality. An understanding of the complex interplay between the aortic valve and LV function would lead to (i) a better understanding of ventricular performance in the presence of AR, and (ii) the development of better clinical metrics for the stratification of the severity of AR. An in vivo approach to addressing these issues would be difficult due to the very high variability in the stages of the disease as well as the multiple confounders that exist. Therefore, developing and utilizing an in vitro system would permit excellent control of the experimental environment, allowing for flexibility and accuracy in studying the isolated and combined effects of AR on LV function, which in turn enables reliable metrics, for the accurate assessment and stratification of AR, to be assessed. To this end, three specific aims were evaluated to address these issues. In specific aim 1, a novel physiological left heart simulator was developed to replicate healthy left heart conditions as well as the pathophysiological progression from healthy to chronic AR conditions. The simulator was capable of matching a multitude of in vivo hemodynamic states for a healthy heart and a left heart inflicted with AR. In specific aim 2, an understanding of the fluid mechanics of AR within the LV was developed. It was discovered that the AR regurgitant jet generates a “kinematic wall” which causes the rapid dissipation of the “normal” flow features which exist within a healthy LV. This discovery lead to the idea that energy dissipation rate could be used as a metric to more accurately stratify AR, which it did, in a nonlinear manner. In specific aim 3, the hemodynamic effects of acute and chronic AR on LV performance were evaluated. Also in this aim, some of the common metrics utilized for the stratification of AR severity were evaluated. The pathophysiological changes which occur to the LV, in particular, the increase diastolic stiffness, was found to affect the metrics used to stratify AR, reduce LV filling, increase LV diastolic pressures, and increase the amount of work the LV needs to accommodate for the lost forward volume resulting from AR. Considered as a whole, the generated data and knowledge from this thesis will contribute to the overall understanding of LV performance in the presence of AR as well as aid in the development of optimal surgical interventional timing strategies for the most effective treatment of patients with AR.