bims-hafaim 2024-12-29 papers

Issue of 2024–12–29
four papers selected by
Kyle McCommis, Saint Louis University

J Am Heart Assoc. 2024 Dec 24. e038461

Cardiovascular and Metabolic Effects of Modulating Circulating Ketone Bodies With 1,3-Butanediol in Patients With Heart Failure With Reduced Ejection Fraction.

Halvor Guldbrandsen, Nigopan Gopalasingam, Kristian Hylleberg Christensen, Oskar Kjærgaard Hørsdal, Roni Nielsen, Henrik Wiggers, Kristoffer Berg-Hansen.

BACKGROUND: Oral treatment with the exogenous ketone body 3-hydroxybutyrate improves cardiac function in patients with heart failure with reduced ejection fraction, but ketosis is limited to 3 to 4 hours. Treatment with (R)-1,3-butanediol (BD) provides prolonged ketosis in healthy controls, but the hemodynamic and metabolic profile is unexplored in patients with heart failure with reduced ejection fraction.
METHODS AND RESULTS: This was a randomized, single-blind, placebo-controlled, crossover study. Transthoracic echocardiography and venous blood samples were performed at baseline and hourly for 6 hours after an oral dose of BD (0.5 g/kg) or taste-matched placebo. The primary end point was the average between-treatment difference in cardiac output during the 6-hour period after intake. Secondary end points were stroke volume, heart rate, left ventricular ejection fraction, circulating 3-hydroxybutyrate, and free fatty acids. Twelve patients with heart failure with reduced ejection fraction were included. BD treatment provided significant increase in circulating 3-hydroxybutyrate by 1400 μmol/L (95% CI, 1262-1538 μmol/L, P<0.001) and increased cardiac output by 0.9 L/min (95% CI, 0.7-1.1 L/min, P<0.001) compared with placebo. Stroke volume increased by 15 mL (95% CI, 11-19 mL, P<0.001), and heart rate remained similar between treatments (P=0.150). Left ventricular ejection fraction increased by 3 percentage points (95% CI, 1-4 percentage points, P<0.001). Global longitudinal strain improved (P<0.001). Left ventricular contractility estimates increased after BD intake, and parameters of afterload were reduced. Finally, free fatty acids and glucose levels decreased.
CONCLUSIONS: Oral dosing of BD led to prolonged ketosis and cardiovascular and metabolic benefits in patients with heart failure with reduced ejection fraction. Treatment with BD is an attractive option to achieve beneficial effects from sustained therapeutic ketosis.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05768100.

Keywords: cardiac output; echocardiography; heart failure; hemodynamics; ketone bodies

DOI: https://doi.org/10.1161/JAHA.124.038461

Pharmacol Res. 2024 Dec 20. pii: S1043-6618(24)00500-0. [Epub ahead of print]211 107555

Intercellular Mitochondrial transfer: Therapeutic implications for energy metabolism in heart failure.

Huan He, Weiwei Huang, Zigang Pan, Lingjun Wang, Zhongqi Yang, Zixin Chen.

Heart failure (HF) remains one of the leading causes of high morbidity and mortality globally. Impaired cardiac energy metabolism plays a critical role in the pathological progression of HF. Various forms of HF exhibit marked differences in energy metabolism, particularly in mitochondrial function and substrate utilization. Recent studies have increasingly highlighted that improving energy metabolism in HF patients as a crucial treatment strategy. Mitochondrial transfer is emerging as a promising and precisely regulated therapeutic strategy for treating metabolic disorders. This paper specifically reviews the characteristics of mitochondrial energy metabolism across different types of HF and explores the modes and mechanisms of mitochondrial transfer between different cell types in the heart, such as cardiomyocytes, fibroblasts, and immune cells. We focused on the therapeutic potential of intercellular mitochondrial transfer in improving energy metabolism disorders in HF. We also discuss the role of signal transduction in mitochondrial transfer, highlighting that mitochondria not only function as energy factories but also play crucial roles in intercellular communication, metabolic regulation, and tissue repair. This study provides new insights into improving energy metabolism in heart failure patients and proposes promising new therapeutic strategies.

Keywords: Cardiomyocyte repair; Energy metabolism; Heart failure; Mitochondrial transfer; Regenerative therapy

DOI: https://doi.org/10.1016/j.phrs.2024.107555

Front Cardiovasc Med. 2024 ;11 1494882

SGLT2 inhibitors for alleviating heart failure through non-hypoglycemic mechanisms.

Ya-Ru Chen, Fang-Yuan Zhu, Rong Zhou.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors afford significant cardiovascular benefits to patients with diabetes mellitus and heart failure. Three large randomized clinical trials (EMPAREG-Outcomes, DECLARE-TIMI58, and DAPA-HF) have shown that SGLT2 inhibitors prevent cardiovascular events and reduce the risk of death and hospital admission resulting from heart failure. Patients without type 2 diabetes mellitus (T2DM) also experience a similar degree of cardiovascular benefit as those with T2DM do. SGLT2 inhibitors could improve cardiac function through potential non-hypoglycemic mechanisms, including the reduction of the circulatory volume load, regulation of energy metabolism, maintenance of ion homeostasis, alleviation of inflammation and oxidative stress, and direct inhibition of cardiac SGLT1 receptors and antimyocardial fibrosis. This article reviews the mechanism through which SGLT2 inhibitors prevent/alleviate heart failure through non-hypoglycemic pathways, to support their use for the treatment of heart failure in non-T2DM patients.

Keywords: cardiovascular outcome trials; dapagliflozin; empagliflozin; heart failure; non-diabetic; sodium-glucose cotransporter-2 inhibitor

DOI: https://doi.org/10.3389/fcvm.2024.1494882

Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Dec 19. pii: S1388-1981(24)00140-9. [Epub ahead of print] 159590

Hippo pathway activation causes multiple lipid derangements in a murine model of cardiomyopathy.

Wei Wu, Kevin Huynh, Jin-Chan Du, Gang She, Thy Duong, Mark Ziemann, Wei-Bo Zhao, Xiu-Ling Deng, Peter J Meikle, Xiao-Jun Du.

Metabolic reprogramming occurs in cardiomyopathy and heart failure contributing to progression of the disease. Activation of cardiac Hippo pathway signaling has been implicated in mediating mitochondrial dysfunction and metabolic reprogramming in cardiomyopathy, albeit influence of Hippo pathway on lipid profile is unclear. Using a dual-omics approach, we determined alterations of cardiac lipids in a mouse model of cardiomyopathy due to enhanced Hippo signaling and explored molecular mechanisms. Lipidomic profiling discovered multiple alterations in lipid classes, notably reduction of triacylglycerol, diacylglycerol, phospholipids and ether lipids, and elevation of sphingolipids and lysophosphatidylcholine. Mechanistically, we found downregulated expression of PPARα and PGC-1α at mRNA and protein levels, and downregulated expression of PPARα-target genes, indicating attenuated transcriptional activity of PPARα/PGC-1α. Lipidomics-guided transcriptomic analysis revealed dysregulated expression of gene sets that were responsible for enhanced biosynthesis of ceramides, suppression of TG biosynthesis, storage, hydrolysis and mitochondrial fatty acid oxidation, and reduction of peroxisome-localized biosynthesis of ether lipids. Collectively, Hippo pathway activation with attenuated PPARα/PGC-1α signaling is the underlying mechanism for alterations in cardiac lipids in cardiomyopathy and failing heart.

Keywords: Cardiomyopathy; Hippo pathway; Lipidomics; Mitochondria; PPARα; Sphingolipids; Transcriptomics; Triglyceride

DOI: https://doi.org/10.1016/j.bbalip.2024.159590