• Therapeutic Potential? Ketone Bodies Linked to Ischemia and Reperfusion Outcomes

    Higher levels of ketone bodies (KBs) 24 hours after ST-segment elevation myocardial infarction (STEMI) are associated with functional outcomes, according to new research that suggests increased ketone metabolism could play a role in the response to myocardial ischemia.

    Published online Monday and in the Oct. 5 issue of the Journal of the American College of Cardiology, the study noted that multiple studies have shown that circulating KBs are increased in patients with heart failure (HF) and that this corresponds with increased cardiac KB metabolism and HF severity.

    However, the role of circulating KBs in ischemia/reperfusion remains unknown, said the researchers, led by Marie-Sophie L.Y. de Koning, MD, from the University of Groningen, the Netherlands.

    As a result, de Koning and colleagues investigated longitudinal changes of KBs in patients who presented with a first STEMI and underwent primary PCI.

    “To the best of our knowledge, we were the first to investigate and report data on the association between circulating KBs and functional outcomes after MI,” said the authors, adding that better understanding of the mechanisms linking ketone metabolism with myocardial ischemia and reperfusion could provide opportunities for therapeutic intervention.

    “We observed that KBs were increased at time of presentation with STEMI,” they reported.

    “Moreover, higher KB concentrations 24 hours after reperfusion were independently associated with larger infarct size and lower LVEF at 4-month follow-up.”

    Study details

    The authors analyzed KB measurements in 369 participants from a randomized trial on early metformin therapy after STEMI.

    Non-fasting plasma concentrations of KBs (b-hydroxybutyrate, acetoacetate and acetone) were measured by nuclear magnetic resonance spectroscopy at presentation, at 24 hours and after 4 months. Meanwhile, myocardial infarct size and left ventricular ejection fraction (LVEF) were determined by cardiac magnetic resonance imaging at 4 months.

    They reported that circulating KBs were high at presentation with STEMI (median total KBs: 520 mmol/L; interquartile range [IQR]: 315-997 mmol/L).

    At 24 hours after reperfusion, KBs were still high compared with levels at 4-month follow-up (206 mmol/L [IQR: 174-246] vs 166 mmol/L [IQR: 143-201], respectively; P < 0.001).

    Using multivariable linear regression analyses, the authors also reported that increased KB concentrations at 24 hours were independently associated with larger myocardial infarct size (total KBs, per 100 mmol/L: β = 1.56; 95% confidence interval [CI]: 0.29-2.83; P = 0.016) and lower LVEF (β = -1.78; 95% CI: -3.17 to -0.39; P = 0.012).

    “We did not observe any associations between KBs at admission and outcomes,” said de Koning and colleagues. “A possible explanation is that KB levels at baseline were substantially driven by the initial adrenergic stress response in all patients after MI, and this might have masked associations between KBs at admission and functional outcomes after STEMI.”

    Our results indicate that ischemia/reperfusion is associated with an increase in KB bioavailability, and that this increase in KBs at 24 hours is associated with impaired functional outcomes,” they added, noting that the results uncover a novel role for ketone metabolism in the systemic response to myocardial ischemia, “which is likely to be adaptive.”

    Therapeutic potential?

    Writing in an accompanying editorial, Salva R. Yurista, MD, PhD; Anthony Rosenzweig, MD; and Christopher T. Nguyen, PhD, from the Corrigan Minehan Heart Center at Massachusetts General Hospital, Boston, noted that there has been “significant” interest in the role of KBs over the past decade, both within and outside the medical arena, because of their reported beneficial effects in the heart.

    “The investigators are to be praised for performing meticulous collection, analyses, and interpretation of the data, as well measurement of KB concentrations in fed subjects without diabetes to avoid the confounding effects of diabetes and overnight fasting,” said the expert commentators, adding that the outcomes of the study form “an essential basis” for our understanding of the role of KBs in ischemia/reperfusion.

    The editorialists added that the increased circulating ketone concentrations and/or myocardial ketone oxidation reported by de Koning and colleagues have also seen in other clinical contexts, including HF with reserved and preserved ejection fraction, diabetes and arrhythmogenic cardiomyopathy.

    “Taken together, these observations suggest a ketogenic shift is a common cardiac response to stress,” they said. “Increased KB concentrations may serve as biomarkers that are associated with disease severity at least in some contexts.”

    They added that although the current study was designed to reveal associations, and did not test the functional effects of KBs after STEMI, there are several reasons to believe modulating cardiac ketone oxidation by increasing KB availability could have therapeutic benefits in STEMI.

    “These include the well-documented and substantial changes that occur in cardiac energy metabolism during ischemia, the supplemental metabolic substrate and potential pleiotropic cardiac effects of KBs, and the positive impact of circulating KB levels on cardiac ketone oxidation rates,” they noted.

    However, they added that although the appeal of enhancing KBs as a therapeutic approach is “understandable,” further rigorous preclinical and clinical studies would be required to test such a therapeutic hypothesis and determine the mechanisms contributing to any benefits observed.

    “Future research with larger sample sizes and an appropriate control group could fruitfully validate the kinds of conclusions that can be drawn from this study,” the commentators noted.

    “Furthermore, incorporation of direct measurement of cardiac arterio-venous KB gradients into future studies would enable assessment of human KB use and production in STEMI, providing additional insights into the mechanisms underlying dynamic regulation of this important metabolic pathway in STEMI.”

    Sources:

    de Koning MSLY, Westenbrink BD, Assa S, et al. Association of Circulating Ketone Bodies With Functional Outcomes After ST-Segment Elevation Myocardial Infarction. J Am Coll Cardiol 2021;78:1421-1432.

    Yurista SR, Rosenzweig A, Nguyen CT. Ketone Bodies: Universal Cardiac Response to Stress? J Am Coll Cardiol 2021;78:133-1436.

    Image Credit: jarun011 – stock.adobe.com

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