Myocardial Ketone Metabolism in Heart Failure
Creators: Ho, Kim
Publisher: name: University of Alberta Library
Year: 2023

<p>Heart failure is a condition whereby the weakened cardiac muscle can no longer pump blood to the rest of the body, resulting in decreased quality of life. Despite the severity of this debilitating condition, there is no cure for heart failure. Modulation of cardiac energy metabolism has become an enticing therapeutic candidate to treat heart failure because the failing heart is energetically starved and metabolically inefficient. However, there is no definitive metabolic profile for the failing heart and recent evidence has emerged suggesting that the failing heart relies more on ketones, prompting the question of whether ketones are good or bad news for the failing heart. Therefore, the focus of my thesis is on the role of ketone metabolism in the setting of heart failure. The first objective was to define a metabolic profile for the failing heart. The second objective was to assess cardiac metabolism and efficiency in response to acute increases in ketone concentration in a healthy heart. The final objective was to assess cardiac function and metabolism following a chronic increase in ketones, via a ketogenic diet, to a failing heart. I hypothesized that if the failing heart has acute or chronic increases in ketone oxidation, this would be protective and mitigate further pathophysiological metabolic and structural remodeling of the failing heart. </p>

<p>To investigate the first objective, C57BL/6J mice underwent a sham or transverse aortic constriction surgery to induce pressure overload hypertrophy. Next, their hearts were excised and subjected to an isolated working heart perfusion to assess the failing heart’s overall cardiac metabolism, function, and efficiency. To investigate the second objective, hearts from healthy mice were subjected to an isolated working heart perfusion and received increasing concentrations of ketones to assess the acute effect of increasing ketone delivery on cardiac metabolism of other substrates, cardiac function and efficiency. Finally, the third objective was addressed by using mice that underwent a sham or left anterior descending coronary artery permanent ligation surgery to induce ischemic heart failure. Following the surgery, mice were randomized to receive a control or ketogenic diet for three weeks. Serial echocardiography was used to assess in vivo cardiac function and at the end of treatment, hearts were excised and subjected to an isolated working heart perfusion. </p>

<p>Hearts from mice with pressure overload hypertrophy exhibited decreased cardiac function alongside an abnormal metabolic profile compared to hearts from healthy mice. The observed failing heart’s metabolic profile displayed decreases in absolute glucose oxidation rates, increases in normalized rates of fatty acid and ketone body oxidation. Furthermore, these metabolic changes contributed to the failing heart’s decreased cardiac efficiency. </p>

<p>In healthy murine hearts perfused with increasing concentrations of ketones, myocardial ketone oxidation rates increased in a concentration-dependent manner with no effect on glucose or fatty acid oxidation rates. Furthermore, elevated ketone oxidation rates increased overall ATP production though this was not accompanied by changes in cardiac work, implying that an accumulation of reduced equivalents could be due to mitochondrial uncoupling. As a result, cardiac efficiency trended to decrease in hearts that were exposed to higher ketone concentrations.</p>

<p>In hearts from mice with ischemic heart failure, implementation of a ketogenic diet did not improve cardiac function compared to mice with heart failure fed a control diet. Furthermore, hearts from mice on the ketogenic diet displayed a notable shift to fatty acids for ATP production which was accompanied by blunted myocardial glucose oxidation rates (even in the presence of insulin). The increased reliance on fatty acids for energy contributed to the observed decrease in cardiac efficiency in heart failure mice fed a ketogenic diet.</p>

<p>My thesis has made several key advances for the field: firstly, the failing heart has blunted glucose oxidation and relies more on ketones for energy; secondly, ketones can increase cardiac ATP production without competing with glucose or fatty acids but do not improve cardiac efficiency; thirdly, the ketogenic diet is not a valid approach to increase myocardial ketone body oxidative rates and instead, shifts the heart’s reliance on energy to fatty acids, causing a secondary decrease in myocardial glucose oxidation rates. Altogether, my thesis has revealed that ketones cannot acutely or chronically improve cardiac function and efficiency of the failing heart.</p>