bims-hafaim 2024-01-14 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2024–01–14
nine papers selected by
Kyle McCommis, Saint Louis University

Mitochondrial fatty acid oxidation is the major source of cardiac ATP production in heart failure with preserved ejection fraction.
Energy metabolism and redox balance: How phytochemicals influence heart failure treatment.
Metabolic status differentiates Trp53inp2 function in pressure-overload induced heart failure.
Protein lysine acetylation does not contribute to the high rates of fatty acid oxidation seen in the post-ischemic heart.
Circulating 3-hydroxy butyrate predicts mortality in patients with chronic heart failure with reduced ejection fraction.
Effects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation.
The Therapeutic Potential of Ketones in Cardiometabolic Disease: Impact on Heart and Skeletal Muscle.
Editorial: Cardiac energetic efficiency and cardiometabolic diseases.
Chapter 3: Clinical Trials of Sodium-Glucose Co-Transporter-2 Inhibitors for Treatment of Heart Failure.

Cardiovasc Res. 2024 Jan 09. pii: cvae006. [Epub ahead of print]

Mitochondrial fatty acid oxidation is the major source of cardiac ATP production in heart failure with preserved ejection fraction.

Qiuyu Sun, Berna Güven, Cory S Wagg, Amanda A de Oliveira, Heidi Silver, Liyan Zhang, Brandon Chen, Kaleigh Wei, Ezra Ketema, Qutuba G Karwi, Kaya L Persad, Jennie Vu, Faqi Wang, Jason R B Dyck, Gavin Y Oudit, Gary D Lopaschuk.

   AIMS: Heart failure with preserved ejection fraction (HFpEF) is a prevalent disease worldwide. While it is well established that alterations of cardiac energy metabolism contribute to cardiovascular pathology, the precise source of fuel used by the heart in HFpEF remain unclear.The objective of this study was to define the energy metabolic profile of the heart in HFpEF.
METHODS AND RESULTS: 8-week-old C57BL/6 male mice were subjected to a '2-Hit' HFpEF protocol (60% high-fat diet (HFD) + 0.5 g/L of Nω-nitro-L-arginine methyl ester (L-NAME)). Echocardiography and pressure-volume loop analysis were used for assessing cardiac function and cardiac hemodynamics respectively. Isolated working hearts were perfused with radiolabeled energy substrates to directly measure rates of fatty acid oxidation, glucose oxidation, ketone oxidation, and glycolysis.HFpEF mice exhibited increased body weight, glucose intolerance, elevated blood pressure, diastolic dysfunction, and cardiac hypertrophy. In HFpEF hearts, insulin stimulation of glucose oxidation was significantly suppressed. This is paralleled with an increase in fatty acid oxidation rates, while cardiac ketone oxidation and glycolysis rates were comparable to healthy control hearts. The balance between glucose and fatty acid oxidation contributing to overall adenosine triphosphate (ATP) production was disrupted, where HFpEF hearts were more reliant on fatty acid as the major source of fuel for ATP production, compensating for the decrease of ATP originating from glucose oxidation. Additionally, p-PDH (pyruvate dehydrogenase) levels decreased in both HFpEF mice and human patients heart samples.
CONCLUSIONS: In HFpEF, fatty acid oxidation dominates as the major source of cardiac ATP production at the expense of insulin stimulated glucose oxidation.

Keywords:  cardiac energy metabolism; fatty acid oxidation; glucose oxidation; glycolysis; ketone oxidation

DOI:  https://doi.org/10.1093/cvr/cvae006
Biomed Pharmacother. 2024 Jan 11. pii: S0753-3322(24)00017-9. [Epub ahead of print]171 116136

Energy metabolism and redox balance: How phytochemicals influence heart failure treatment.

Cong Chen, Jie Wang, Xueying Zhu, Jun Hu, Chao Liu, Lanchun Liu.

  Heart Failure (HF) epitomizes a formidable global health quandary characterized by marked morbidity and mortality. It has been established that severe derangements in energy metabolism are central to the pathogenesis of HF, culminating in an inadequate cardiac energy milieu, which, in turn, precipitates cardiac pump dysfunction and systemic energy metabolic failure, thereby steering the trajectory and potential recuperation of HF. The conventional therapeutic paradigms for HF predominantly target amelioration of heart rate, and cardiac preload and afterload, proffering symptomatic palliation or decelerating the disease progression. However, the realm of therapeutics targeting the cardiac energy metabolism remains largely uncharted. This review delineates the quintessential characteristics of cardiac energy metabolism in healthy hearts, and the metabolic aberrations observed during HF, alongside the associated metabolic pathways and targets. Furthermore, we delve into the potential of phytochemicals in rectifying the redox disequilibrium and the perturbations in energy metabolism observed in HF. Through an exhaustive analysis of recent advancements, we underscore the promise of phytochemicals in modulating these pathways, thereby unfurling a novel vista on HF therapeutics. Given their potential in orchestrating cardiac energy metabolism, phytochemicals are emerging as a burgeoning frontier for HF treatment. The review accentuates the imperative for deeper exploration into how these phytochemicals specifically intervene in cardiac energy metabolism, and the subsequent translation of these findings into clinical applications, thereby broadening the horizon for HF treatment modalities.

Keywords:  Energy metabolism; Glucose oxidation; Heart failure; Mitochondria; Phytochemicals

DOI:  https://doi.org/10.1016/j.biopha.2024.116136
Front Cardiovasc Med. 2023 ;10 1226586

Metabolic status differentiates Trp53inp2 function in pressure-overload induced heart failure.

Jianfang Liu, Tian Liu, Shuxun Vincent Ren, Cansheng Zhu, Eyad Bouso, Samir Mamlouk, Christoph D Rau, Yibin Wang, Chen Gao.

  Cardiometabolic disorders encompass a broad range of cardiovascular complications associated with metabolic dysfunction. These conditions have an increasing share in the health burden worldwide due to worsening endemic of hypertension, obesity, and diabetes. Previous studies have identified Tumor Protein p53-inducible Nuclear Protein 2 (Trp53inp2) as a molecular link between hyperglycemia and cardiac hypertrophy. However, its role in cardiac pathology has never been determined in vivo. In this study, we generated a cardiac specific knockout model of Trp53inp2 (Trp53inp2-cKO) and investigated the impact of Trp53inp2 inactivation on the pathogenesis of heart failure under mechanic or/and metabolic stresses. Based on echocardiography assessment, inactivation of Trp53inp2 in heart led to accelerated onset of HFrEF in response to pressure-overload, with significantly reduced ejection fraction and elevated heart failure marker genes comparing to the control mice. In contrast, inactivation of Trp53inp2 ameliorated cardiac dysfunction induced by combined stresses of high fat diet and moderate pressure overload (Cardiometabolic Disorder Model). Moreover, Trp53inp2 inactivation led to reduced expression of glucose metabolism genes in lean, pressure-overloaded hearts. However, the same set of genes were significantly induced in the Trp53inp2-cKO hearts under both mechanical and metabolic stresses. In summary, we have demonstrated for the first time that cardiomyocyte Trp53inp2 has diametrically differential roles in the pathogenesis of heart failure and glucose regulation under mechanical vs. mechanical plus metabolic stresses. This insight suggests that Trp53inp2 may exacerbate the cardiac dysfunction during pressure overload injury but have a protective effect in cardiac diastolic function in cardiometabolic disease.

Keywords:  Trp53inp2; cardiometabolic syndrome; glucose metabolism; heart failure; transcription factor

DOI:  https://doi.org/10.3389/fcvm.2023.1226586
Sci Rep. 2024 Jan 12. 14(1): 1193

Protein lysine acetylation does not contribute to the high rates of fatty acid oxidation seen in the post-ischemic heart.

Ezra B Ketema, Muhammad Ahsan, Liyan Zhang, Qutuba G Karwi, Gary D Lopaschuk.

High rates of cardiac fatty acid oxidation during reperfusion of ischemic hearts contribute to contractile dysfunction. This study aimed to investigate whether lysine acetylation affects fatty acid oxidation rates and recovery in post-ischemic hearts. Isolated working hearts from Sprague Dawley rats were perfused with 1.2 mM palmitate and 5 mM glucose and subjected to 30 min of ischemia and 40 min of reperfusion. Cardiac function, fatty acid oxidation, glucose oxidation, and glycolysis rates were compared between pre- and post-ischemic hearts. The acetylation status of enzymes involved in cardiac energy metabolism was assessed in both groups. Reperfusion after ischemia resulted in only a 41% recovery of cardiac work. Fatty acid oxidation and glycolysis rates increased while glucose oxidation rates decreased. The contribution of fatty acid oxidation to ATP production and TCA cycle activity increased from 90 to 93% and from 94.9 to 98.3%, respectively, in post-ischemic hearts. However, the overall acetylation status and acetylation levels of metabolic enzymes did not change in response to ischemia and reperfusion. These findings suggest that acetylation may not contribute to the high rates of fatty acid oxidation and reduced glucose oxidation observed in post-ischemic hearts perfused with high levels of palmitate substrate.

DOI: https://doi.org/10.1038/s41598-024-51571-0
ESC Heart Fail. 2024 Jan 09.

Circulating 3-hydroxy butyrate predicts mortality in patients with chronic heart failure with reduced ejection fraction.

Kristian Hylleberg Christensen, Roni R Nielsen, Morten Schou, Ida Gustafsson, Anders Jorsal, Allan Flyvbjerg, Lise Tarnow, Hans Erik Bøtker, Caroline Kistorp, Mogens Johannsen, Niels Møller, Henrik Wiggers.

   AIMS: In patients with chronic heart failure with reduced ejection fraction (HFrEF), myocardial ketone metabolism is increased and short-term treatment with the ketone body 3-hydroxy butyrate (3-OHB) has beneficial haemodynamic effects. In patients with HFrEF, we investigated whether the level of circulating 3-OHB predicted all-cause mortality and sought to identify correlations between patient characteristics and circulating 3-OHB levels.
METHODS AND RESULTS: We conducted a cohort study in 218 patients with HFrEF. Plasma 3-OHB levels were measured using high-performance liquid chromatography tandem mass spectrometry. Data on all-cause mortality were obtained by reviewing the patients' medical records, which are linked to the national 'Central Person Registry' that registers the timing of all deaths in the country. Mean left ventricular ejection fraction was 35 ± 8.6%, mean age was 67 ± 10 years, 54% were New York Heart Association II, and 27% had type 2 diabetes mellitus. Median follow-up time was 7.3 (interquartile range 6.3-8.4) years. We observed large variations in 3-OHB levels between patients (median 59 μM, range: 14-694 μM). Patients with 3-OHB levels above the median displayed a markedly increased risk of death compared with those with low levels {hazard ratio [HR]: 2.1 [95% confidence interval (CI): 1.3-3.5], P = 0.003}. In a multivariate analysis, 3-OHB predicted mortality independently of known chronic heart failure risk factors [HR: 1.004 (95% CI: 1.001-1.007), P = 0.02] and with a similar statistical strength as N-terminal pro-brain natriuretic peptide (NT-proBNP) [HR: 1.0005 (95% CI: 1.000-1.001), P = 0.02]. For every 100 μmol increase in plasma 3-OHB, the hazard of death increased by 49%. The following factors significantly predicted 3-OHB levels in the univariate analysis: free fatty acids (FFAs) [β: 238 (95% CI: 185-292), P < 0.0001], age [β: 2.43 (95% CI: 1.14-3.72), P < 0.0001], plasma insulin {β: -0.28 [95% CI: -0.54-(-0.02)], P = 0.036}, body mass index {β: -3.15 [95% CI: -5.26-(-0.05)], P = 0.046}, diabetes [β: 44.49 (95% CI: 14.84-74.14), P = 0.003], glycosylated haemoglobin [β: 1.92 (95% CI: 0.24-3.59), P = 0.025], New York Heart Association class [β: 26.86 (95% CI: 5.99-47.72), P = 0.012], and NT-proBNP [β: 0.03 (95% CI: 0.01-0.04), P = 0.001]. In a multivariate analysis, only FFAs predicted 3-OHB levels [β: 216 (95% CI: 165-268), P > 0.001].
CONCLUSIONS: In patients with HFrEF, circulating 3-OHB was a strong predictor of all-cause mortality independently of NT-proBNP. Circulating FFAs were the best predictor of 3-OHB levels.

Keywords:  3-Hydroxy butyrate; Heart failure; Ketone bodies; Metabolism; Prognosis

DOI:  https://doi.org/10.1002/ehf2.14476
Sci Rep. 2024 01 08. 14(1): 757

Effects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation.

Jacob Marthinsen Seefeldt, Yaara Libai, Katrine Berg, Nichlas Riise Jespersen, Thomas Ravn Lassen, Frederik Flyvholm Dalsgaard, Pia Ryhammer, Michael Pedersen, Lars Bo Ilkjaer, Michiel A Hu, Michiel E Erasmus, Roni R Nielsen, Hans Erik Bøtker, Oren Caspi, Hans Eiskjær, Niels Moeslund.

Normothermic regional perfusion (NRP) allows assessment of therapeutic interventions prior to donation after circulatory death transplantation. Sodium-3-hydroxybutyrate (3-OHB) increases cardiac output in heart failure patients and diminishes ischemia-reperfusion injury, presumably by improving mitochondrial metabolism. We investigated effects of 3-OHB on cardiac and mitochondrial function in transplanted hearts and in cardiac organoids. Donor pigs (n = 14) underwent circulatory death followed by NRP. Following static cold storage, hearts were transplanted into recipient pigs. 3-OHB or Ringer's acetate infusions were initiated during NRP and after transplantation. We evaluated hemodynamics and mitochondrial function. 3-OHB mediated effects on contractility, relaxation, calcium, and conduction were tested in cardiac organoids from human pluripotent stem cells. Following NRP, 3-OHB increased cardiac output (P < 0.0001) by increasing stroke volume (P = 0.006), dP/dt (P = 0.02) and reducing arterial elastance (P = 0.02). Following transplantation, infusion of 3-OHB maintained mitochondrial respiration (P = 0.009) but caused inotropy-resistant vasoplegia that prevented weaning. In cardiac organoids, 3-OHB increased contraction amplitude (P = 0.002) and shortened contraction duration (P = 0.013) without affecting calcium handling or conduction velocity. 3-OHB had beneficial cardiac effects and may have a potential to secure cardiac function during heart transplantation. Further studies are needed to optimize administration practice in donors and recipients and to validate the effect on mitochondrial function.

DOI: https://doi.org/10.1038/s41598-024-51387-y
Am J Physiol Cell Physiol. 2024 Jan 09.

The Therapeutic Potential of Ketones in Cardiometabolic Disease: Impact on Heart and Skeletal Muscle.

Shubham Soni, Seyed Amirhossein Tabatabaei Dakhili, John R Ussher, Jason R B Dyck.

  β-hydroxybutyrate (βOHB) is the major ketone in the body and it is recognized as a metabolic energy source and an important signaling molecule. While ketone oxidation is essential in the brain during prolonged fasting/starvation, other organs such as skeletal muscle and the heart also use ketones as metabolic substrates. Additionally, βOHB-mediated molecular signaling events occur in heart and skeletal muscle cells, and via metabolism and/or signaling, ketones may contribute to optimal skeletal muscle health and cardiac function. Of importance, when the use of ketones for ATP production and/or as signaling molecules becomes disturbed in the presence of underlying obesity, type 2 diabetes and/or cardiovascular diseases, these changes may contribute to cardiometabolic disease. As a result of these disturbances in cardiometabolic disease, multiple approaches have been used to elevate circulating ketones with the goal of improving either ketone metabolism or ketone-mediated signaling. These approaches have produced significant improvements in heart and skeletal muscle during cardiometabolic disease with a wide range of benefits that include improved metabolism, weight loss, better glycemic control, improved cardiac and vascular function, as well as reduced inflammation and oxidative stress. Herein, we present the evidence that indicates that ketone therapy could be used as an approach to help treat cardiometabolic diseases by targeting cardiac and skeletal muscle.

Keywords:  cardiovascular disease; diabetes; heart failure; ketone bodies; β-hydroxybutyrate

DOI:  https://doi.org/10.1152/ajpcell.00501.2023
Front Cardiovasc Med. 2023 ;10 1352798

Editorial: Cardiac energetic efficiency and cardiometabolic diseases.

Teresa Vanessa Fiorentino, Francesca Cinti, Ram Jagannathan.



Keywords:  cardiac energetics; cardiac metabolism; cardiac performance; cardiovascular disease; myocardial efficiency

DOI:  https://doi.org/10.3389/fcvm.2023.1352798
Am J Med. 2024 Feb;pii: S0002-9343(23)00290-5. [Epub ahead of print]137(2S): S25-S34

Chapter 3: Clinical Trials of Sodium-Glucose Co-Transporter-2 Inhibitors for Treatment of Heart Failure.

Stephen J Greene, Javed Butler, Mikhail N Kosiborod.

  Cardiovascular outcomes trials of sodium-glucose co-transporter-2 (SGLT2) inhibitors have demonstrated consistent signals of benefit in terms of both prevention and treatment of heart failure (HF), in patients with and without type 2 diabetes (T2D). In response to growing evidence of the benefits of SGLT2 inhibitors, including increased survival, reduced hospitalizations and improved patient-reported symptoms, functional status, and quality of life, the treatment landscape for HF has evolved. Importantly, these agents have also demonstrated safety and tolerability in individuals with HF across the spectrum of left ventricular ejection fraction, with improvements in clinical and patient-reported outcomes occurring as early as days to weeks after treatment initiation. For patients with heart failure with reduced ejection fraction (HFrEF), SGLT2 inhibitors are now increasingly recognized as foundational disease-modifying therapy. An updated joint guideline from the American College of Cardiology and American Heart Association now recommends including SGLT2 inhibitors for patients with HF across the spectrum of ejection fraction, irrespective of the presence of diabetes, and regardless of background therapy (Class 1 recommendation for HFrEF, Class 2a recommendation for HF with mildly reduced ejection fraction [HFmrEF] and HF with preserved ejection fraction [HFpEF]). The European Society of Cardiology also include a Class I recommendation to use SGLT2 inhibitors for patients with HFrEF to reduce the risk of hospitalization for HF and CV death, irrespective of T2D status. This chapter reviews published clinical trial data about the efficacy and safety of SGLT2 inhibitors among patients with HFrEF, HFpEF, and patients hospitalized for HF.

Keywords:  Cardiovascular outcomes; Heart failure; Hospitalization; Sodium-glucose co-transporter 2 inhibitors

DOI:  https://doi.org/10.1016/j.amjmed.2023.04.019