Improving our Understanding of Experimental Heart Failure and the Prevalent Secondary Condition, Type II Pulmonary Hypertension

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Date

2019-02-01

Authors

Platt, Mathew

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Publisher

University of Guelph

Abstract

Heart failure (HF), a chronic disease present in 15% of adults over 65, is a leading cause of mortality in the developed world. With a rising prevalence and a mortality rate of ~50% within 5 years of diagnosis, HF is urgently in need of improved management strategies. Developing these strategies requires an improved understanding of how HF develops to identify novel ways to prevent this progression. Additionally, there is a growing clinical appreciation for the role of the right ventricle (RV) and the lungs in HF; namely the development of secondary pulmonary hypertension (PH) in HF and its relationship to patient mortality. Critically, there are no standard-of-care therapies for PH in HF despite a prevalence as high as 85%. The aims of this thesis were to improve our understanding of how HF develops over time from the perspective of both ventricles and the lungs, and to investigate a therapeutic option for the unmanaged prevalent condition of PH in HF. We hypothesize that (1) our model of HF (pressure-overload via aortic banding) will develop RV dysfunction and pulmonary remodeling that is not predictable from the remodeling patterns observed in the LV, and (2) that PH can be treated by currently available cardiovascular drugs if they are assessed for their impact on the RV and lungs. Temporal characterization of LV and RV function identified TAC as a model of PH secondary to elevated LV filling pressures; a condition known as type II PH. This longitudinal approach identified unique patterns of hypertrophy, dysfunction and hemodynamics between the LV and RV, emphasizing the need to investigate both ventricles to understand the overall cardiac phenotype. Further, correlations at individual timepoints were inconsistent over time, underscoring the complexity of relationships and the inability to draw conclusions about how HF develops from timepoints in isolation. These findings further our understanding of the murine pressure-overload model of HF, particularly as it relates to its usefulness as a model of type II PH. We also found that common lipophilic cardiovascular drugs treated type II PH, presenting a possible therapeutic option for this unmanaged patient population.

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Keywords

pulmonary hypertension, heart failure, animal models, aortic constriction, right ventricle, pressure overload, lipophilic

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