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Circulating ketone bodies (KBs) are substantially elevated at presentation and 24 hours after ST-segment elevation myocardial infarction (STEMI), according to new research.

The study also showed that greater KB levels measured after 24 hours of reperfusion were associated with larger infarct size and reduced left ventricular ejection fraction (LVEF).

The findings suggest a potential role for ketone metabolism in response to myocardial ischemia, conclude researchers in their report, published in the October 5 issue of the Journal of the American College of Cardiology.

Marie-Sophie de Koning

“Ketones serve as an alternative source of energy for the heart,” lead author Marie-Sophie L.Y. de Koning, MD, University Medical Center Groningen, the Netherlands, told | Medscape Cardiology.

“These results might suggest that ketone bodies may be an important fuel for the heart after myocardial ischemia.” The role of KBs in heart failure has been previously studied, but their role in myocardial infarction has not, amaryl patient assistance program de Koning said.

“In heart failure, metabolic changes occur that cause the heart to increasingly rely on ketone bodies as an important energy source. Accordingly, concentrations of circulating ketone bodies are elevated and higher concentrations have been linked with more severe heart failure,” she said.

“This might suggest that upregulation of ketone metabolism is a universal cardiac response to stress,” de Koning added. “But the role of ketone bodies in myocardial infarction remained largely unknown, and this triggered us to investigate circulating ketone bodies in patients presenting with STEMI.”

She and her team measured circulating KBs in archived plasma samples from 369 participants in the randomized GIPS-III trial. The study had primarily looked at the effect of 4 months of metformin therapy, compared with placebo, on LVEF in nondiabetic patients with a first STEMI.

Blood samples had been taken at baseline before percutaneous coronary intervention (PCI), at 24 hours after reperfusion, and at 4 months.

The current study investigated longitudinal post-STEMI changes in the circulating KBs beta-hydroxybutyrate, acetoacetate, and acetone. It also looked at associations of KBs with infarct size and LVEF, both of which were measured with cardiac magnetic resonance (CMR) imaging 4 months after STEMI.

Circulating KB levels were three time higher at STEMI presentation than at 4 months. At presentation, the median total KB level was 520 μmol/L. It was still higher 24 hours after reperfusion than at 4 months (206 vs 166 μmol/L; P < .001).

The 24-hour KB elevations were independently and positively associated with larger infarct size (P = .016) and lower LVEF (P = .012), the group reports.

“Our results indicate a possible role for ketone bodies during myocardial infarction,” de Koning said.

The KB elevations were probably followed by “an increase in cardiac ketone body metabolism, in order to fuel the heart that is energetically depleted.”

But the study didn’t explore cardiac KB consumption, de Koning cautioned, adding that the next steps in this research should be to investigate post-STEMI cardiac ketone metabolism and its pathophysiologic mechanisms. “This may facilitate future trials to study therapeutic effects of ketone body supplementation during or after STEMI.”

Salva Yurista

The current findings “form an essential basis for our understanding of the role of KBs in ischemia/reperfusion,” write Salva R. Yurista, MD, PhD, and colleagues, Massachusetts General Hospital and Harvard Medical School, Boston, in an accompanying editorial.

“Although the appeal of enhancing KBs as a therapeutic approach is understandable, additional rigorous preclinical and clinical studies will be required to test this therapeutic hypothesis and determine the mechanisms contributing to any benefits observed,” they note.

“Exposure to cardiac stress, such as ischemia, infarction, or heart failure, will stimulate the release of neurohormones, pro-inflammatory cytokines, and natriuretic peptides, which may play roles in stimulating ketogenesis or the production of ketone bodies,” Yurista told | Medscape Cardiology.

The increased circulating ketone concentrations and myocardial ketone oxidation that were associated with poor functional outcomes have been reported in other clinical contexts, including heart failure with reduced ejection fraction, heart failure with preserved cardiac function, diabetic cardiomyopathy, and arrhythmogenic cardiomyopathy, he said.

Yurista agrees that KBs could have therapeutic merit.

“Circulating ketone concentrations determine the contribution of ketones to the cardiac diet,” he said. “Thus, increasing cardiac delivery of ketone bodies through supplementation or other means to the heart undergoing stress, including STEMI and heart failure, could have therapeutic potential.”

The GIPS-III trial was supported by the Netherlands Organization for Health Research and Development (ZonMw). Neither de Koning nor the other authors report relevant financial relationships. Yurista and the other editorialists report no relevant relationships.

J Am Coll Cardiol. 2021;78:1421-1432, 1433-1436. Abstract, Editorial

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