The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense
Julie L. Horton, Michael T. Davidson, Clara Kurishima, Rick B. Vega, Jeffery C. Powers, Timothy R. Matsuura, Christopher Petucci, E. Douglas Lewandowski, Peter A. Crawford, Deborah M. Muoio, Fabio A. Recchia, Daniel P. Kelly
Julie L. Horton, Michael T. Davidson, Clara Kurishima, Rick B. Vega, Jeffery C. Powers, Timothy R. Matsuura, Christopher Petucci, E. Douglas Lewandowski, Peter A. Crawford, Deborah M. Muoio, Fabio A. Recchia, Daniel P. Kelly
View: Text | PDF
Research Article Cardiology Metabolism

The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense

Abstract

Evidence has emerged that the failing heart increases utilization of ketone bodies. We sought to determine whether this fuel shift is adaptive. Mice rendered incapable of oxidizing the ketone body 3-hydroxybutyrate (3OHB) in the heart exhibited worsened heart failure in response to fasting or a pressure overload/ischemic insult compared with WT controls. Increased delivery of 3OHB ameliorated pathologic cardiac remodeling and dysfunction in mice and in a canine pacing model of progressive heart failure. 3OHB was shown to enhance bioenergetic thermodynamics of isolated mitochondria in the context of limiting levels of fatty acids. These results indicate that the heart utilizes 3OHB as a metabolic stress defense and suggest that strategies aimed at increasing ketone delivery to the heart could prove useful in the treatment of heart failure.

Authors

Julie L. Horton, Michael T. Davidson, Clara Kurishima, Rick B. Vega, Jeffery C. Powers, Timothy R. Matsuura, Christopher Petucci, E. Douglas Lewandowski, Peter A. Crawford, Deborah M. Muoio, Fabio A. Recchia, Daniel P. Kelly

×

Figure 4

Chronically increased delivery of ketone bodies to the heart by direct infusion ameliorates pathological cardiac remodeling.

Options: View larger image (or click on image) Download as PowerPoint
Chronically increased delivery of ketone bodies to the heart by direct i...
(A) Results of echocardiography and hemodynamic monitoring at weeks 0, 2, and 4 of tachypacing in dogs without (HF) or with infusion of 3-hydroxybuytrate (HF + 3OHB). Note that the “2 week” echo was performed on day 14 for the HF dogs, and — for the HF+3OHB group — the echo was performed on days 12–13 immediately before starting 3OHB infusion. The set of data for HF was randomly selected from a historical pool. (B) β-Adrenergic response to dobutamine infused after 4 weeks of cardiac pacing. Dots and bars represent mean ± SEM (n = 7–8 per group), *P < 0.05 vs. baseline or #P < 0.05 HF vs. HF + 3OHB at the corresponding time point using 2-way ANOVA followed by Student-Newman test for multiple comparisons. HR, heart rate; EF, ejection fraction; CO, cardiac output; LVEDP, left ventricular end-diastolic pressure; LVEDD, left ventricular end-diastolic diameter; TPR, total peripheral resistance; Ea, effective arterial elastance; dP/dtmax, maximal first derivative of left ventricular pressure.