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Protein pool turnover is a critically important cellular homeostatic component, yet it has been little explored in the context of heart failure (HF) pathophysiology. We used in vivo 2 H labeling/proteome dynamics for the nonbiased discovery of turnover alterations involving functionally linked cardiac and plasma proteins in canine tachypacing-induced HF, an established preclinical model of dilated cardiomyopathy. Compared with controls, dogs with congestive HF displayed bidirectional turnover changes of 28 cardiac proteins, that is, a reduced half-life of several key enzymes involved in glycolysis, homocysteine metabolism and glycogenesis, and increased half-life of proteins involved in proteolysis. Changes in plasma proteins were more modest: only 5 proteins, involved in various functions including proteolysis inhibition, hemoglobin, calcium and ferric iron binding, displayed increased or decreased turnover rates. In other dogs undergoing cardiac tachypacing, we infused for 2 weeks the myokine Follistatin-like protein 1, known for its ameliorative effects on HF-induced alterations. Proteome dynamics proved very sensitive in detecting the partial or complete prevention, by Follistatin-like protein 1, of cardiac and plasma protein turnover alterations. In conclusion, our study unveiled, for the first time in a large mammal, numerous HF-related alterations that may serve as the basis for future mechanistic research and/or as conceptually new molecular markers., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: FSTL1 (follistatin-like protein 1) is an emerging cardiokine/myokine that is upregulated in heart failure (HF) and is found to be cardioprotective in animal models of cardiac injury. We tested the hypothesis that circulating FSTL1 can affect cardiac function and metabolism under baseline physiological conditions and in HF., Methods and Results: FSTL1 was acutely (10 minutes) or chronically (2 weeks) infused to attain clinically relevant blood levels in conscious dogs with cardiac tachypacing-induced HF. Dogs with no cardiac pacing and FSTL1 infusion served as control. 3 H-oleate and 14 C-glucose were infused to track the metabolic fate of free fatty acids and glucose. Cardiac uptake of lactate and ketone bodies and systemic respiratory quotient were also measured. HF caused a shift from prevalent cardiac and systemic fat to carbohydrate oxidation. Although acute FSTL1 administration caused minimal hemodynamic changes at baseline, in HF dogs it enhanced cardiac oxygen consumption and transiently reversed the changes in free fatty acid and glucose oxidation and systemic respiratory quotient. In HF, chronic FSTL1 infusion stably normalized cardiac free fatty acid, glucose, ketone body consumption, and systemic respiratory quotient, while moderately improving diastolic and contractile function. Consistently, FSTL1 prevented the downregulation of medium-chain acyl-CoA dehydrogenase-a representative enzyme of the free fatty acid oxidation pathway. Complementary in vitro experiments in primary cardiac and skeletal muscle myocytes showed that FSTL1 stimulated oxygen consumption through AMPK (AMP-activated kinase) activation., Conclusions: These findings support a novel function for FSTL1 and provide the first direct evidence that a circulating cardiokine/myokine can alter myocardial and systemic energy substrate metabolism, in vivo., (© 2018 American Heart Association, Inc.)

Introduction: Recent Evidence indicates that circulating ketone bodies serve as an alternative myocardial substrate in heart failure (HF). Hypothesis: We tested the hypothesis that enhancing ketones delivery to the heart during early/compensated stages of HF delays the progression towards decompensation. Methods: Eight chronically instrumented dogs were subjected to cardiac tachypacing and infused with the ketone beta-hydroxybutyrate (BHB), starting after 2 weeks of pacing (HF+BHB group), i.e. during the early stages of cardiac dysfunction. A group of 8 dogs was subjected to cardiac pacing without BHB infusion (HF group). In 5 dogs per group, paired blood samples were withdrawn from aorta and coronary sinus to measure cardiac substrate utilization. 3H-oleate and 14C-glucose were co-infused to track the metabolic fate of free fatty acids (FFA) and glucose. Results: Blood BHB concentrations reached 190.3±19.7 microM in HF+BHB, approximately 4-fold the normal baseline values. This enhanced cardiac ketone uptake from 0.0091±0.002 to 0.022±0.005 umol/beat/100gr in HF+BHB vs HF (P<0.05). Cardiac glucose oxidation was more than doubled in HF vs control and but was suppressed in HF+BHB together with a 60% reduction in lactate uptake (all P<0.05). In contrast, FFA oxidation rates were modestly increased by the BHB infusion. These metabolic alterations were associated with marked functional protection: after 29±1 days of cardiac pacing, LV end-diastolic pressure was ≥25 mmHg in HF, indicating end-stage decompensation, while it remained at normal physiological values in HF+BHB. Cardiac output was also preserved and the fall in ejection fraction was significantly attenuated (56.1±1.5 vs 37.0±3.1%, P<0.05) in HF+BHB compared to HF. Beta-adrenergic response to dobutamine was also significantly higher in HF+BHB. However, BHB did not prevent alterations of other hemodynamic parameters, such as systemic blood pressures and dP/dtmax/min, typically occurring in HF. Conclusions: These results provide the first evidence that high levels of circulating BHB exert strong beneficial effects in HF opposing the progression toward decompensation, perhaps in part due to the shift of failing hearts from carbohydrate to ketones as a major source of energy. [ABSTRACT FROM AUTHOR]