Metabolic Therapy of Heart Failure: Is There a Future for B Vitamins?

Heart failure (HF) is a plague of the aging population in industrialized countries that continues to cause many deaths despite intensive research into more effective treatments. Although the therapeutic arsenal to face heart failure has been expanding, the relatively short life expectancy of HF patients is pushing towards novel therapeutic strategies. Heart failure is associated with drastic metabolic disorders, including severe myocardial mitochondrial dysfunction and systemic nutrient deprivation secondary to severe cardiac dysfunction. To date, no effective therapy has been developed to restore the cardiac energy metabolism of the failing myocardium, mainly due to the metabolic complexity and intertwining of the involved processes. Recent years have witnessed a growing scientific interest in natural molecules that play a pivotal role in energy metabolism with promising therapeutic effects against heart failure. Among these molecules, B vitamins are a class of water soluble vitamins that are directly involved in energy metabolism and are of particular interest since they are intimately linked to energy metabolism and HF patients are often B vitamin deficient. This review aims at assessing the value of B vitamin supplementation in the treatment of heart failure.

Disruption of Glycolysis, TCA Cycle, Respiratory Chain, Calcium and Iron Homeostasis in Doxorubicin Induced Cardiomyopathy-An In-silico Approach

Doxorubicin is a well-known anthracycline antibiotic that is frequently used to treat a variety of malignancies. However, its clinical use is limited due to its adverse consequences, most notably cardiomyopathy. In the present work, we evaluated the molecular mechanisms behind the impairment of cardiac energetics in doxorubicin-induced cardiomyopathy. According to molecular docking, the interaction of doxorubicin with phosphofructokinase (PKF) and α-enolase is likely to negatively affect glycolysis. The interaction between doxorubicin with HMOX1 results in the accumulation of free iron. The free iron contributes to the heme-driven toxicity and the oxidizing environment that results in reactive oxygen species (ROS) production resulting from cell death. Additionally, the interaction of doxorubicin with HMOX1 impairs the availability of iron required for the Krebs cycle and ETC function. The interaction between doxorubicin and PINK1 results in a reduced membrane potential, which results in calcium accumulation. On the other hand, a lack of iron and calcium in the mitochondrial matrix results in ATP depletion, impairing the Krebs cycle activity. At the same time, the primary cause of doxorubicin-induced cardiomyopathy is cardiac energy metabolism. Thus, our work shows that doxorubicin impairs the activity of PFK, α-enolase, HMOX1, and PINK1, resulting in ATP production failure. As a result of changes in the heart energy metabolism, this ultimately leads to dilated cardiomyopathy caused by doxorubicin. Understanding the critical function of cardiac energy metabolism in doxorubicin-induced cardiomyopathy is critical for overcoming the obstacles that effectively limit the clinical effectiveness of this life-saving anti-cancer treatment.

Effects of Lipid Overload on Heart in Metabolic Diseases

Metabolic diseases are often associated with lipid and glucose metabolism abnormalities, which increase the risk of cardiovascular disease. Diabetic cardiomyopathy (DCM) is an important development of metabolic diseases and a major cause of death. Lipids are the main fuel for energy metabolism in the heart. The increase of circulating lipids affects the uptake and utilization of fatty acids and glucose in the heart, and also affects mitochondrial function. In this paper, the mechanism of lipid overload in metabolic diseases leading to cardiac energy metabolism disorder is discussed.

Global and Regional Myocardial Work in Female Adolescents with Weight Disorders

Background: Anorexia nervosa (AN) and obesity (OB) lead to changes in SBP (i.e., loading conditions) that may affect left ventricular (LV) myocardial work (MW). The novel concept of LV pressure-strain loops allows non-invasive estimation of MW, this latter being correlated with cardiac energy metabolism. In addition, the study of regional MW can detect subtle alterations in cardiac function by highlighting an abnormal distribution of MW. Objective: The aim of this study was to assess the cardiac function of AN and OB patients by evaluating global and regional LV strains and MW. Methods: Eighty-seven female adolescents, comprising 26 with AN (14.6 ± 1.9 yrs. old), 28 with OB (13.2 ± 1.4 yrs. old), and 33 controls (14.0 ± 2.0 yrs. old) underwent speckle-tracking echography to assess global and regional LV strains and MW. Results: SBP was higher in adolescents with obesity than in AN patients or controls. Global MW was similar between groups. In AN patients and controls, longitudinal strains were higher at the apex than at the base of the LV, whereas they were similar in obesity patients, owing to a decrease in their apical longitudinal strain. Consequently, their MW was higher at the basal level than either of the other two groups (1854 ± 272 vs. 1501 ± 280 vs. 1575 ± 295 mmHg% in OB patients, AN patients, and controls, respectively. Conclusion: Despite altered SBP, the global MW of adolescents with weight disorders was unaffected. However, in adolescents with obesity, the distribution of their regional LV MW was altered, which might reflect specific regional remodeling.

Creatine deficiency and heart failure

Impaired cardiac energy metabolism has been proposed as a mechanism common to different heart failure aetiologies. The energy-depletion hypothesis was pursued by several researchers, and is still a topic of considerable interest. Unlike most organs, in the heart, the creatine kinase system represents a major component of the metabolic machinery, as it functions as an energy shuttle between mitochondria and cytosol. In heart failure, the decrease in creatine level anticipates the reduction in adenosine triphosphate, and the degree of myocardial phosphocreatine/adenosine triphosphate ratio reduction correlates with disease severity, contractile dysfunction, and myocardial structural remodelling. However, it remains to be elucidated whether an impairment of phosphocreatine buffer activity contributes to the pathophysiology of heart failure and whether correcting this energy deficit might prove beneficial. The effects of creatine deficiency and the potential utility of creatine supplementation have been investigated in experimental and clinical models, showing controversial findings. The goal of this article is to provide a comprehensive overview on the role of creatine in cardiac energy metabolism, the assessment and clinical value of creatine deficiency in heart failure, and the possible options for the specific metabolic therapy.

Post-translational Acetylation Control of Cardiac Energy Metabolism

Perturbations in myocardial energy substrate metabolism are key contributors to the pathogenesis of heart diseases. However, the underlying causes of these metabolic alterations remain poorly understood. Recently, post-translational acetylation-mediated modification of metabolic enzymes has emerged as one of the important regulatory mechanisms for these metabolic changes. Nevertheless, despite the growing reports of a large number of acetylated cardiac mitochondrial proteins involved in energy metabolism, the functional consequences of these acetylation changes and how they correlate to metabolic alterations and myocardial dysfunction are not clearly defined. This review summarizes the evidence for a role of cardiac mitochondrial protein acetylation in altering the function of major metabolic enzymes and myocardial energy metabolism in various cardiovascular disease conditions.

Cardiac Energy Metabolism in Heart Failure

Alterations in cardiac energy metabolism contribute to the severity of heart failure. However, the energy metabolic changes that occur in heart failure are complex and are dependent not only on the severity and type of heart failure present but also on the co-existence of common comorbidities such as obesity and type 2 diabetes. The failing heart faces an energy deficit, primarily because of a decrease in mitochondrial oxidative capacity. This is partly compensated for by an increase in ATP production from glycolysis. The relative contribution of the different fuels for mitochondrial ATP production also changes, including a decrease in glucose and amino acid oxidation, and an increase in ketone oxidation. The oxidation of fatty acids by the heart increases or decreases, depending on the type of heart failure. For instance, in heart failure associated with diabetes and obesity, myocardial fatty acid oxidation increases, while in heart failure associated with hypertension or ischemia, myocardial fatty acid oxidation decreases. Combined, these energy metabolic changes result in the failing heart becoming less efficient (ie, a decrease in cardiac work/O 2 consumed). The alterations in both glycolysis and mitochondrial oxidative metabolism in the failing heart are due to both transcriptional changes in key enzymes involved in these metabolic pathways, as well as alterations in NAD redox state (NAD + and nicotinamide adenine dinucleotide levels) and metabolite signaling that contribute to posttranslational epigenetic changes in the control of expression of genes encoding energy metabolic enzymes. Alterations in the fate of glucose, beyond flux through glycolysis or glucose oxidation, also contribute to the pathology of heart failure. Of importance, pharmacological targeting of the energy metabolic pathways has emerged as a novel therapeutic approach to improving cardiac efficiency, decreasing the energy deficit and improving cardiac function in the failing heart.

Abstract 15649: Pharmacological Inhibition of Aldose Reductase by AT001 Prevents Abnormal Cardiac Energy Metabolism and Improves Heart Function in an Animal Model of Diabetic Cardiomyopathy

Introduction: Diabetic Cardiomyopathy (DCM) is a major cause of death in people with type 2 diabetes (T2D). Alterations in cardiac energy metabolism including increased fatty acid oxidation rates and reduced glucose oxidation rates are key contributing factors to the development of DCM. Studies have shown that Aldose Reductase (AR), an enzyme activated under hyperglycemic conditions, can modulate myocardial glucose and fatty acid oxidation, and promotes cardiac dysfunction. Hypothesis: Pharmacological inhibition of AR using a next-generation inhibitor AT-001, can mitigate DCM in mice by modulating cardiac energy metabolism and improving cardiac efficiency. Methods: Male human AR overexpressing (hAR-Tg) and C57BL/6J (Control) mice were subjected to experimental T2D (high-fat diet [60% kcal from lard] for 10-wk with a single intraperitoneal streptozotocin injection of 75 mg/kg) and treated for the last 3-wk with AT-001 (40mg/kg/day) or vehicle via oral gavage. Cardiac energy metabolism and in vivo cardiac function were assessed via isolated working heart perfusions and ultrasound echocardiography, respectively. Results: AT-001 treatment significantly improved cardiac energetics in a murine model of DCM (hAR-Tg mice with T2D). Particularly, AT-001-treated mice exhibited decreased cardiac fatty acid oxidation rates compared to the vehicle-treated mice (342 ± 53 vs 964 ± 130 nmol/min/g dry wt.). Concurrently, there was a significant decrease in cardiac oxygen consumption in the AT-001-treated compared to the vehicle-treated mice (41 ± 12 vs 60 ± 11 μmol/min/g dry wt.), suggesting increased cardiac efficiency. Furthermore, treatment with AT-001 prevented cardiac structural and functional abnormalities present in DCM, including diastolic dysfunction as reflected by an increase in the tissue Doppler E’/A’ ratio and decrease in E/E’ ratio. Moreover, AT-001 treatment prevented cardiac hypertrophy as reflected by a decrease in LV mass in AT-001-treated mice. Conclusions: AR inhibition with AT-001 prevents cardiac structural and functional abnormalities in a mouse model of DCM, and normalizes cardiac energetics by shifting cardiac metabolism towards a non-diabetic metabolic state.