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Assessment of Cardiac Energy Metabolism, Function, and Physiology in Patients With Heart Failure Taking
Moritz J Hundertmark1,2, Amanda Adler3, Charalambos Antoniades4
1Oxford Centre for Clinical Magnetic Resonance Research (M.J.H., H.L., S.M., F.E.M., B.R., O.R., C.T.R., L.V., M.M., S.N.), Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, UK.
Insights
Sodium-glucose co-transporter 2 inhibitors (SGLT2i) did not improve cardiac energy metabolism in heart failure patients. This study suggests that enhanced energy production is unlikely to be the mechanism behind SGLT2i benefits in heart failure.
Area of Science:
- Cardiology
- Metabolic Disorders
- Pharmacology
Background:
- Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are effective for heart failure (HF) but their cardiac mechanism is unclear.
- Myocardial energy metabolism is impaired in all HF types, suggesting SGLT2i might improve energy production.
Purpose of the Study:
- To investigate if empagliflozin alters myocardial energetics, serum metabolomics, and cardiorespiratory fitness in HF patients.
- To explore the potential mechanism of SGLT2i in treating heart failure.
Main Methods:
- A prospective, randomized, double-blind, placebo-controlled trial (EMPA-VISION) involving 72 HF patients (HFrEF and HFpEF).
- Patients received 10 mg empagliflozin or placebo daily for 12 weeks.
- Cardiac energetics (PCr/ATP) were measured using phosphorus magnetic resonance spectroscopy during rest and dobutamine stress; serum metabolomics were also analyzed.
Main Results:
- Empagliflozin did not significantly change cardiac energetics (PCr/ATP) at rest or during stress in either HFrEF or HFpEF groups compared to placebo.
- No significant changes were observed in serum metabolomics or circulating ketone bodies.
Conclusions:
- Empagliflozin treatment for 12 weeks did not improve cardiac energetics or alter serum metabolites related to energy metabolism in HF patients.
- These findings indicate that enhanced cardiac energy metabolism is unlikely to mediate the beneficial effects of SGLT2i in heart failure.
Background:
Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a paramount treatment for patients with heart failure (HF), irrespective of underlying reduced or preserved ejection fraction. However, a definite cardiac mechanism of action remains elusive. Derangements in myocardial energy metabolism are detectable in all HF phenotypes, and it was proposed that SGLT2i may improve energy production. The authors aimed to investigate whether treatment with empagliflozin leads to changes in myocardial energetics, serum metabolomics, and cardiorespiratory fitness.
Methods:
EMPA-VISION (Assessment of Cardiac Energy Metabolism, Function and Physiology in Patients With Heart Failure Taking Empagliflozin) is a prospective, randomized, double-blind, placebo-controlled, mechanistic trial that enrolled 72 symptomatic patients with chronic HF with reduced ejection fraction (HFrEF; n=36; left ventricular ejection fraction ≤40%; New York Heart Association class ≥II; NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥125 pg/mL) and HF with preserved ejection fraction (HFpEF; n=36; left ventricular ejection fraction ≥50%; New York Heart Association class ≥II; NT-proBNP ≥125 pg/mL). Patients were stratified into respective cohorts (HFrEF versus HFpEF) and randomly assigned to empagliflozin (10 mg; n=35: 17 HFrEF and 18 HFpEF) or placebo (n=37: 19 HFrEF and 18 HFpEF) once daily for 12 weeks. The primary end point was a change in the cardiac phosphocreatine:ATP ratio (PCr/ATP) from baseline to week 12, determined by phosphorus magnetic resonance spectroscopy at rest and during peak dobutamine stress (65% of age-maximum heart rate). Mass spectrometry on a targeted set of 19 metabolites was performed at baseline and after treatment. Other exploratory end points were investigated.
Results:
Empagliflozin treatment did not change cardiac energetics (ie, PCr/ATP) at rest in HFrEF (adjusted mean treatment difference [empagliflozin - placebo], -0.25 [95% CI, -0.58 to 0.09]; P=0.14) or HFpEF (adjusted mean treatment difference, -0.16 [95% CI, -0.60 to 0.29]; P=0.47]. Likewise, there were no changes in PCr/ATP during dobutamine stress in HFrEF (adjusted mean treatment difference, -0.13 [95% CI, -0.35 to 0.09]; P=0.23) or HFpEF (adjusted mean treatment difference, -0.22 [95% CI, -0.66 to 0.23]; P=0.32). No changes in serum metabolomics or levels of circulating ketone bodies were observed.
Conclusions:
In patients with either HFrEF or HFpEF, treatment with 10 mg of empagliflozin once daily for 12 weeks did not improve cardiac energetics or change circulating serum metabolites associated with energy metabolism when compared with placebo. Based on our results, it is unlikely that enhancing cardiac energy metabolism mediates the beneficial effects of SGLT2i in HF.
Registration:
URL: https://www.
Clinicaltrials:
gov; Unique identifier: NCT03332212.
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