Date on Master's Thesis/Doctoral Dissertation

8-2025

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Physiology and Biophysics

Degree Program

Physiology and Biophysics, PhD

Committee Chair

Hill, Bradford G.

Committee Co-Chair (if applicable)

Nystoriak, Matthew

Committee Member

Jones, Steven P.

Committee Member

Metz, Cynthia

Committee Member

Brainard, Robert

Committee Member

Carll, Alex P.

Author's Keywords

cardiovascular; exercise; microcirculation; beta-hydroxybutyrate; coronary; ketone bodies

Abstract

Cardiorespiratory fitness, a crucial determinant of overall health and a strong predictor of all-cause mortality, is largely dependent on the capacity of the cardiovascular system to deliver oxygen and nutrients. The heart, as the central pump, requires a continuous and adaptable oxygen supply, particularly during increased workload such as occurs with exercise. Impaired myocardial blood flow (MBF) in response to increased demand can lead to ischemia, limiting exercise capacity and potentially causing severe cardiac events. Interestingly, changes in myocardial metabolism and cardiac work correlate with changes in MBF. Therefore, understanding the regulation of MBF, especially the link between local cardiac metabolism and blood flow, is vital for developing interventions to improve cardiovascular health and exercise tolerance, particularly in conditions associated with impaired microvascular function such as cardiovascular disease and aging. Recent clinical studies have indicated that MBF is markedly affected by the ketone body, 3-hydroxybutyrate (3-OHB). Endogenously produced by the liver, 3-OHB is the most abundant ketone body in circulation. Not only has acute administration of 3-OHB been found to enhance MBF, but it is also capable of augmenting exercise capacity. Although previous studies have demonstrated that the availability of substrates such as 3-OHB influences MBF, the extent to which their myocardial metabolism drives the hyperemic response remains unclear and how metabolic changes in the heart influence physical endurance is unknown. As 3-OHB is readily taken up and used as fuel by cardiomyocytes, 3-OHB administration provides a novel avenue for studying how changes myocardial metabolism are linked to MBF and cardiac function. The following study assessed how altering local cardiac metabolism, specifically through the administration of 3-OHB, influences exercise capacity and myocardial hyperemia. As such, our overarching hypothesis was that ketone body-evoked increases in exercise capacity and myocardial perfusion are, at least in part, due to indirect signaling resulting from the catabolism of 3-OHB within cardiomyocytes. Chapter II addressed the effect of cardiomyocyte ketone body metabolism on 3-OHB-mediated exercise capacity. This work demonstrated that while the absence of 3-hydroxybutyrate dehydrogenase (BDH1), an enzyme essential for 3-OHB oxidation in cardiomyocytes, did not impact baseline exercise capacity, it abolished the improvement in exercise performance following exogenous ketone body supplementation. These findings strongly support the hypothesis that the ergogenic effects of ketones during hyperketonemia require their oxidation within cardiomyocytes. Chapter III further addressed the extent to which ketone bodies alter myocardial hyperemia and delineated the extent to which this phenomenon relied on cardiomyocyte ketone body metabolism as opposed to direct action on the vascular smooth muscle. In this chapter, we showed that 3-OHB infusion significantly increased myocardial perfusion in wild-type mice, but this effect was not replicated by direct administration of physiological concentrations of 3-OHB to isolated coronary arteries. Rather, the 3-OHB-induced hyperemic response was abolished in mice with cardiomyocyte-specific deletion of BDH1. This provides compelling evidence that the enhanced myocardial perfusion observed with 3-OHB is dependent on its metabolism within cardiomyocytes. Collectively, these findings provide significant evidence that the beneficial effects of ketone bodies on exercise capacity and myocardial perfusion are mediated through their catabolism in cardiomyocytes, advancing our understanding of the link between cardiac metabolism and cardiovascular function

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