In heart failure, myocardial overload causes vast metabolic changes that impair cardiac energy production and contribute to deterioration of contractile function. However, metabolic therapy is not used in heart failure care. We aimed to investigate the interplay between cardiac function and myocardial carbohydrate metabolism in a large animal heart failure model. Using magnetic resonance spectroscopy with hyperpolarized pyruvate and magnetic resonance imaging at rest and during pharmacological stress, we investigated the in-vivo cardiac pyruvate metabolism and contractility in a porcine model of chronic pulmonary insufficiency causing right ventricular volume overload. To assess if increasing the carbohydrate metabolic reserve improves the contractile reserve, a group of animals were fed dichloroacetate, an activator of pyruvate oxidation. Volume overload caused heart failure with decreased pyruvate dehydrogenase flux and poor ejection fraction reserve. The animals treated with dichloroacetate had a larger contractile response to dobutamine stress than non-treated animals. Further, dichloroacetate prevented myocardial hypertrophy. The in-vivo metabolic data were validated by mitochondrial respirometry, enzyme activity assays and gene expression analyses. Our results show that pyruvate dehydrogenase kinase inhibition improves the contractile reserve and decreases hypertrophy by augmenting carbohydrate metabolism in porcine heart failure. The approach is promising for metabolic heart failure therapy.
Background
Hyperpolarized (HP) [1-13C]pyruvate cardiovascular magnetic resonance (CMR) imaging can visualize the uptake and intracellular conversion of [1-13C]pyruvate to either [1-13C]lactate or 13C-bicarbonate depending on the prevailing metabolic state. The aim of the present study was to combine an adenosine stress test with HP [1-13C]pyruvate CMR to detect cardiac metabolism in the healthy human heart at rest and during moderate stress.
Methods
A prospective descriptive study was performed between October 2019 and August 2020. Healthy human subjects underwent cine CMR and HP [1-13C]pyruvate CMR at rest and during adenosine stress. HP [1-13C]pyruvate CMR images were acquired at the mid-left-ventricle (LV) level. Semi-quantitative assessment of first-pass myocardial [1-13C]pyruvate perfusion and metabolism were assessed. Paired t-tests were used to compare mean values at rest and during stress.
Results
Six healthy subjects (two female), age 29 ± 7 years were studied and no adverse reactions occurred. Myocardial [1-13C]pyruvate perfusion was significantly increased during stress with a reduction in time-to-peak from 6.2 ± 2.8 to 2.7 ± 1.3 s, p = 0.02. This higher perfusion was accompanied by an overall increased myocardial uptake and metabolism. The conversion rate constant (kPL) for lactate increased from 11 ± 9 *10–3 to 20 ± 10 * 10–3 s−1, p = 0.04. The pyruvate oxidation rate (kPB) increased from 4 ± 4 *10–3 to 12 ± 7 *10–3 s−1, p = 0.008. This increase in carbohydrate metabolism was positively correlated with heart rate (R2 = 0.44, p = 0.02).
Conclusions
Adenosine stress testing combined with HP [1-13C]pyruvate CMR is feasible and well-tolerated in healthy subjects. We observed an increased pyruvate oxidation during cardiac stress. The present study is an important step in the translation of HP [1-13C]pyruvate CMR into clinical cardiac imaging.
Trial registration EUDRACT, 2018-003533-15. Registered 4th of December 2018, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-003533-15
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