Increasing carbohydrate oxidation improves contractile reserves and prevents hypertrophy in porcine right heart failure

Abstract

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.

Cardiac pH-Imaging With Hyperpolarized MRI

“…Only few studies have probed acid-base disturbances in altered physiology or disease. Recently, we confirmed the finding from Lau et al that hyperpolarized [1-13 C]pyruvate detects myocardial acidification during increased workload from dobutamine stress (21,31). In the same paper, we reported that heart failure from right ventricular volume overload decreased myocardial pH in-vivo.…”

“…Apart from technical developments, one critical question remains: Where does pH-imaging fit in the clinic, and which patients may benefit from the technique? Only three studies have investigated the technique in disease models (28,29,31). More are needed to elucidate its potential across the field of cardiology.…”

“…Generally, pH was estimated within the normal range and with good agreement to conventional methods. Due to the relatively low signal-to-noise of the carbon dioxide peak, most studies used spectroscopy of a slice through the ventricles (28,29,31,45). As the heart is much more metabolically active and has larger pyruvate uptake than the surrounding tissue, spectroscopy data of hyperpolarized pyruvate can be assumed to reflect cardiac pH.…”

“…Compared to the considerable work performed in cancer, few studies have investigated hyperpolarized MRI for myocardial pH-estimation. Studies of the healthy ( 21 , 45 , 46 ) as well as the diseased ( 28 , 29 , 31 ) heart have been conducted. All except one ( 46 ) used hyperpolarized pyruvate.…”

Energy Metabolism in Exercise-Induced Physiologic Cardiac Hypertrophy

“…Metabolic remodeling is closely related to the occurrence and development of cardiac hypertrophy and other heart diseases. Exploring the energy metabolism mechanism of cardiomyocytes may lead to new therapeutic targets, which will be helpful to design new effective methods and strategies for the treatment of heart failure ( Bøgh et al., 2020 ; Makrecka-Kuka et al., 2020 ; Zuurbier et al., 2020 ). As we all know, physical exercise has a protective effect on the heart, and can even partially compensate for heart damage and improve heart function.…”