bims-hafaim 2024-03-24 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2024‒03‒24
six papers selected by
Kyle McCommis, Saint Louis University

Metabolic profiling of aortic stenosis and hypertrophic cardiomyopathy identifies mechanistic contrasts in substrate utilization.
Incremental Value of a Metabolic Risk Score for Heart Failure Mortality: A Population-Based Study.
Bioinformatics identifies key genes and potential drugs for energy metabolism disorders in heart failure with dilated cardiomyopathy.
Cardiac phenotype in adolescents and young adults with long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency.
Lactate infusion elevates cardiac output through increased heart rate and decreased vascular resistance: a randomised, blinded, crossover trial in a healthy porcine model.
Obesity: the perfect storm for heart failure.

FASEB J. 2024 Mar 31. 38(6): e23505

Metabolic profiling of aortic stenosis and hypertrophic cardiomyopathy identifies mechanistic contrasts in substrate utilization.

Nikhil Pal, Animesh Acharjee, Zsuzsanna Ament, Tim Dent, Arash Yavari, Masliza Mahmod, Rina Ariga, James West, Violetta Steeples, Mark Cassar, Neil J Howell, Helen Lockstone, Kate Elliott, Parisa Yavari, William Briggs, Michael Frenneaux, Bernard Prendergast, Jeremy S Dwight, Rajesh Kharbanda, Hugh Watkins, Houman Ashrafian, Julian L Griffin.

  Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated. We undertook an invasive (aortic root, coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison with non-LVH controls to investigate cardiac fuel selection and metabolic remodeling. These patients were assessed under different physiological states (at rest, during stress induced by pacing). The identified changes in the metabolome were further validated by metabolomic and orthogonal transcriptomic analysis, in separately recruited patient cohorts. We identified a highly discriminant metabolomic signature in severe AS in all samples, regardless of sampling site, characterized by striking accumulation of long-chain acylcarnitines, intermediates of fatty acid transport across the inner mitochondrial membrane, and validated this in a separate cohort. Mechanistically, we identify a downregulation in the PPAR-α transcriptional network, including expression of genes regulating fatty acid oxidation (FAO). In silico modeling of β-oxidation demonstrated that flux could be inhibited by both the accumulation of fatty acids as a substrate for mitochondria and the accumulation of medium-chain carnitines which induce competitive inhibition of the acyl-CoA dehydrogenases. We present a comprehensive analysis of changes in the metabolic pathways (transcriptome to metabolome) in severe AS, and its comparison to HCM. Our results demonstrate a progressive impairment of β-oxidation from HCM to AS, particularly for FAO of long-chain fatty acids, and that the PPAR-α signaling network may be a specific metabolic therapeutic target in AS.

Keywords:  cardiac gradient; cardiac metabolism; ischemic heart disease; metabolomics; precision medicine

DOI:  https://doi.org/10.1096/fj.202301710RR
Circ Genom Precis Med. 2024 Mar 22. e004312

Incremental Value of a Metabolic Risk Score for Heart Failure Mortality: A Population-Based Study.

Jungnam Joo, Joseph J Shearer, Anna Wolska, Alan T Remaley, James D Otvos, Margery A Connelly, Maureen Sampson, Suzette J Bielinski, Nicholas B Larson, Hoyoung Park, Katherine M Conners, Sarah Turecamo, Véronique L Roger.

  BACKGROUND: Heart failure is heterogeneous syndrome with persistently high mortality. Nuclear magnetic resonance spectroscopy enables high-throughput metabolomics, suitable for precision phenotyping. We aimed to use targeted metabolomics to derive a metabolic risk score (MRS) that improved mortality risk stratification in heart failure.METHODS: Nuclear magnetic resonance was used to measure 21 metabolites (lipoprotein subspecies, branched-chain amino acids, alanine, GlycA, ketone bodies, glucose, and citrate) in plasma collected from a heart failure community cohort. The MRS was derived using LASSO penalized Cox regression and temporal validation. The association between the MRS and mortality and whether risk stratification was improved over the Meta-Analysis Global Group in Chronic Heart Failure clinical risk score and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels were assessed.
RESULTS: The study included 1382 patients (median age, 78 years, 52% men, 43% reduced ejection fraction) with a 5-year survival rate of 48% (95% CI, 46%-51%). The MRS included 9 metabolites measured. In the validation data set, a 1 SD increase in the MRS was associated with a large increased rate of death (hazard ratio, 2.2 [95% CI, 1.9-2.5]) that remained after adjustment for Meta-Analysis Global Group in Chronic Heart Failure score and NT-proBNP (hazard ratio, 1.6 [95% CI, 1.3-1.9]). These associations did not differ by ejection fraction. The integrated discrimination and net reclassification indices, and Uno's C statistic, indicated that the addition of the MRS improved discrimination over Meta-Analysis Global Group in Chronic Heart Failure and NT-proBNP.
CONCLUSIONS: This MRS developed in a heart failure community cohort was associated with a large excess risk of death and improved risk stratification beyond an established risk score and clinical markers.

Keywords:  atrial fibrillation; biomarkers; cardiovascular diseases; heart failure; natriuretic peptide, brain

DOI:  https://doi.org/10.1161/CIRCGEN.123.004312
Front Pharmacol. 2024 ;15 1367848

Bioinformatics identifies key genes and potential drugs for energy metabolism disorders in heart failure with dilated cardiomyopathy.

Haixia Wang, Peifeng Cai, Xiaohan Yu, Shiqi Li, Wei Zhu, Yuntao Liu, Dawei Wang.

  Background: Dysfunction in myocardial energy metabolism plays a vital role in the pathological process of Dilated Cardiomyopathy (DCM). However, the precise mechanisms remain unclear. This study aims to investigate the key molecular mechanisms of energy metabolism and potential therapeutic agents in the progression of dilated cardiomyopathy with heart failure. Methods: Gene expression profiles and clinical data for patients with dilated cardiomyopathy complicated by heart failure, as well as healthy controls, were sourced from the Gene Expression Omnibus (GEO) database. Gene sets associated with energy metabolism were downloaded from the Molecular Signatures Database (MSigDB) for subsequent analysis. Weighted Gene Co-expression Network Analysis (WGCNA) and differential expression analysis were employed to identify key modules and genes related to heart failure. Potential biological mechanisms were investigated through Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and the construction of a competing endogenous RNA (ceRNA) network. Molecular docking simulations were then conducted to explore the binding affinity and conformation of potential therapeutic drugs with hub genes. Results: Analysis of the left ventricular tissue expression profiles revealed that, compared to healthy controls, patients with dilated cardiomyopathy exhibited 234 differentially expressed genes and 2 genes related to myocardial energy metabolism. Additionally, Benzoylaconine may serve as a potential therapeutic agent for the treatment of dilated cardiomyopathy. Conclusion: The study findings highlight the crucial role of myocardial energy metabolism in the progression of Dilated Cardiomyopathy. Notably, Benzoylaconine emerges as a potential candidate for treating Dilated Cardiomyopathy, potentially exerting its therapeutic effects by targeted modulation of myocardial energy metabolism through NRK and NT5.

Keywords:  DCM; NAD+; bioinformatics; energy metabolism disorder; heart failure; key genes; molecular docking; potential drugs

DOI:  https://doi.org/10.3389/fphar.2024.1367848
Genet Med. 2024 Mar 16. pii: S1098-3600(24)00056-X. [Epub ahead of print] 101123

Cardiac phenotype in adolescents and young adults with long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency.

Gabriela Elizondo, Ajesh Saini, Cesar Gonzalez de Alba, Ashley Gregor, Cary O Harding, Melanie B Gillingham, Jeffrey M Vinocur.

  BACKGROUND: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a rare fatty acid oxidation disorder characterized by recurrent episodes of metabolic decompensation and rhabdomyolysis as well as retinopathy, peripheral neuropathy, and cardiac involvement such as infantile dilated cardiomyopathy. As LCHADD patients are surviving longer, we sought to characterize LCHADD-associated major cardiac involvement in adolescence and young adulthood.METHODS: A retrospective cohort of 16 adolescent and young adult participants with LCHADD was reviewed for cardiac phenotype.
RESULTS: Major cardiac involvement occurred in 9 of 16 participants, including sudden death, out-of-hospital cardiac arrest, acute cardiac decompensations with heart failure and/or in-hospital cardiac arrest, end-stage dilated cardiomyopathy, and moderate restrictive cardiomyopathy. Sudden cardiac arrest was more common in males and those with a history of infant cardiomyopathy.
CONCLUSION: The cardiac manifestations of LCHADD in adolescence and early adulthood are complex and distinct from the phenotype seen in infancy. Life-threatening arrhythmia occurs at substantial rates in LCHADD, often in the absence of metabolic decompensation or rhabdomyolysis. The potential risk factors identified here - male gender and history of infant cardiomyopathy -may hint at strategies for risk stratification and possibly prevention of these events.

Keywords:  Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; cardiomyopathy; fatty acid oxidation disorder; sudden cardiac arrest; sudden cardiac death

DOI:  https://doi.org/10.1016/j.gim.2024.101123
J Transl Med. 2024 Mar 16. 22(1): 285

Lactate infusion elevates cardiac output through increased heart rate and decreased vascular resistance: a randomised, blinded, crossover trial in a healthy porcine model.

Oskar Kjærgaard Hørsdal, Niels Moeslund, Kristoffer Berg-Hansen, Roni Nielsen, Niels Møller, Hans Eiskjær, Henrik Wiggers, Nigopan Gopalasingam.

  BACKGROUND: Lactate is traditionally recognized as a by-product of anaerobic metabolism. However, lactate is a preferred oxidative substrate for stressed myocardium. Exogenous lactate infusion increases cardiac output (CO). The exact mechanism underlying this mechanism has yet to be elucidated. The aim of this study was to investigate the cardiovascular mechanisms underlying the acute haemodynamic effects of exogenous lactate infusion in an experimental model of human-sized pigs.METHODS: In this randomised, blinded crossover study in eight 60-kg-pigs, the pigs received infusions with one molar sodium lactate and a control infusion of tonicity matched hypertonic saline in random order. We measured CO and pulmonary pressures using a pulmonary artery catheter. A pressure-volume admittance catheter in the left ventricle was used to measure contractility, afterload, preload and work-related parameters.
RESULTS: Lactate infusion increased circulating lactate levels by 9.9 mmol/L (95% confidence interval (CI) 9.1 to 11.0) and CO by 2.0 L/min (95% CI 1.2 to 2.7). Afterload decreased as arterial elastance fell by -1.0 mmHg/ml (95% CI -2.0 to -0.1) and systemic vascular resistance decreased by -548 dynes/s/cm5 (95% CI -261 to -835). Mixed venous saturation increased by 11 percentage points (95% CI 6 to 16), whereas ejection fraction increased by 16.0 percentage points (95% CI 1.1 to 32.0) and heart rate by 21 bpm (95% CI 8 to 33). No significant changes in contractility nor preload were observed.
CONCLUSION: Lactate infusion increased cardiac output by increasing heart rate and lowering afterload. No differences were observed in left ventricular contractility or preload. Lactate holds potential as a treatment in situations with lowered CO and should be investigated in future clinical studies.

Keywords:  Cardiovascular physiology; Haemodynamics; Heart failure; Lactate; Metabolism; Pressure–volume

DOI:  https://doi.org/10.1186/s12967-024-05064-3
ESC Heart Fail. 2024 Mar 15.

Obesity: the perfect storm for heart failure.

Maria Lembo, Teresa Strisciuglio, Celeste Fonderico, Costantino Mancusi, Raffaele Izzo, Valentina Trimarco, Alessandro Bellis, Emanuele Barbato, Giovanni Esposito, Carmine Morisco, Speranza Rubattu.

  Obesity condition causes morphological and functional alterations involving the cardiovascular system. These can represent the substrates for different cardiovascular diseases, such as atrial fibrillation, coronary artery disease, sudden cardiac death, and heart failure (HF) with both preserved ejection fraction (EF) and reduced EF. Different pathogenetic mechanisms may help to explain the association between obesity and HF including left ventricular remodelling and epicardial fat accumulation, endothelial dysfunction, and coronary microvascular dysfunction. Multi-imaging modalities are required for appropriate recognition of subclinical systolic dysfunction typically associated with obesity, with echocardiography being the most cost-effective technique. Therapeutic approach in patients with obesity and HF is challenging, particularly regarding patients with preserved EF in which few strategies with high level of evidence are available. Weight loss is of extreme importance in patients with obesity and HF, being a primary therapeutic intervention. Sodium-glucose co-transporter-2 inhibitors have been recently introduced as a novel tool in the management of HF patients. The present review aims at analysing the most recent studies supporting pathogenesis, diagnosis, and management in patients with obesity and HF.

Keywords:  Atrial fibrillation; Direct-acting oral anticoagulants; Heart failure; Implantable cardioverter-defibrillators; Left ventricular remodelling; Natriuretic peptides; Obesity; Sacubitril/valsartan; Sodium-glucose co-transporter-2 inhibitors; Sudden cardiac death

DOI:  https://doi.org/10.1002/ehf2.14641