bims-hafaim 2022-04-10 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2022–04–10
six papers selected by
Kyle McCommis, Saint Louis University

BSCL2/Seipin deficiency in hearts causes cardiac energy deficit and dysfunction via inducing excessive lipid catabolism.
A mitochondrial long-chain fatty acid oxidation defect leads to tRNA uncharging and activation of the integrated stress response in the mouse heart.
Sodium-Glucose Cotransporter Inhibitors Reduce Mortality and Morbidity in Patients With Heart Failure: Evidence From a Meta-Analysis of Randomized Trials.
An Effective Sodium-Dependent Glucose Transporter 2 Inhibition, Canagliflozin, Prevents Development of Hypertensive Heart Failure in Dahl Salt-Sensitive Rats.
Ketones regulate endothelial homeostasis.
Comparative Cardiovascular Outcomes of SGLT2 Inhibitors in Type 2 Diabetes Mellitus: A Network Meta-Analysis of Randomized Controlled Trials.

Clin Transl Med. 2022 Apr;12(4): e736

BSCL2/Seipin deficiency in hearts causes cardiac energy deficit and dysfunction via inducing excessive lipid catabolism.

Hongyi Zhou, Jie Li, Huabo Su, Ji Li, Todd A Lydic, Martin E Young, Weiqin Chen.

   BACKGROUND: Heart failure (HF) is one of the leading causes of death worldwide and is associated with cardiac metabolic perturbations. Human Type 2 Berardinelli-Seip Congenital Lipodystrophy (BSCL2) disease is caused by mutations in the BSCL2 gene. Global lipodystrophic Bscl2-/- mice exhibit hypertrophic cardiomyopathy with reduced cardiac steatosis. Whether BSCL2 plays a direct role in regulating cardiac substrate metabolism and/or contractile function remains unknown.
METHODS: We generated mice with cardiomyocyte-specific deletion of Bscl2 (Bscl2cKO ) and studied their cardiac substrate utilisation, bioenergetics, lipidomics and contractile function under baseline or after either a treatment regimen using fatty acid oxidation (FAO) inhibitor trimetazidine (TMZ) or a prevention regimen with high-fat diet (HFD) feeding. Mice with partial ATGL deletion and cardiac-specific deletion of Bscl2 were also generated followed by cardiac phenotyping.
RESULTS: Different from hypertrophic cardiomyopathy in Bscl2-/- mice, mice with cardiac-specific deletion of Bscl2 developed systolic dysfunction with dilation. Myocardial BSCL2 deletion led to elevated ATGL expression and FAO along with reduced cardiac lipid contents. Cardiac dysfunction in Bscl2cKO mice was independent of mitochondrial dysfunction and oxidative stress, but associated with decreased metabolic reserve and ATP levels. Importantly, cardiac dysfunction in Bscl2cKO mice could be partially reversed by FAO inhibitor TMZ, or prevented by genetic abolishment of one ATGL allele or HFD feeding. Lipidomic analysis further identified markedly reduced glycerolipids, glycerophospholipids, NEFA and acylcarnitines in Bscl2cKO hearts, which were partially normalised by TMZ or HFD.
CONCLUSIONS: We identified a new form of cardiac dysfunction with excessive lipid utilisation which ultimately causes cardiac substrate depletion and bioenergetics failure. Our findings also uncover a crucial role of BSCL2 in controlling cardiac lipid catabolism and contractile function and provide novel insights into metabolically treating energy-starved HF using FAO inhibitor or HFD.

Keywords:  BSCL2/Seipin; heart failure; lipid metabolism; lipidomics

DOI:  https://doi.org/10.1002/ctm2.736
Cardiovasc Res. 2022 Apr 07. pii: cvac050. [Epub ahead of print]

A mitochondrial long-chain fatty acid oxidation defect leads to tRNA uncharging and activation of the integrated stress response in the mouse heart.

Pablo Ranea-Robles, Natalya N Pavlova, Aaron Bender, Andrea S Pereyra, Jessica M Ellis, Brandon Stauffer, Chunli Yu, Craig B Thompson, Carmen Argmann, Michelle Puchowicz, Sander M Houten.

   AIMS: Cardiomyopathy and arrhythmias can be severe presentations in patients with inherited defects of mitochondrial long-chain fatty acid β-oxidation (FAO). The pathophysiological mechanisms that underlie these cardiac abnormalities remain largely unknown. We investigated the molecular adaptations to a FAO deficiency in the heart using the long-chain acyl-CoA dehydrogenase (LCAD) knockout (KO) mouse model.
METHODS AND RESULTS: We observed enrichment of amino acid metabolic pathways and of ATF4 target genes among the upregulated genes in the LCAD KO heart transcriptome. We also found a prominent activation of the eIF2α/ATF4 axis at the protein level that was independent of the feeding status, in addition to a reduction of cardiac protein synthesis during a short period of food withdrawal. These findings are consistent with an activation of the integrated stress response (ISR) in the LCAD KO mouse heart. Notably, charging of several tRNAs, such as tRNAGln was decreased in LCAD KO hearts, reflecting a reduced availability of cardiac amino acids, in particular, glutamine. We replicated the activation of the ISR in hearts of mice with a muscle-specific deletion of carnitine palmitoyltransferase 2.
CONCLUSIONS: Our results show that perturbations in amino acid metabolism caused by long-chain FAO deficiency impact on cardiac metabolic signaling, in particular the ISR. These results may serve as a foundation for investigating the role of the ISR in the cardiac pathology associated with long-chain FAO defects.Translational Perspective: The heart relies mainly on mitochondrial fatty acid β-oxidation (FAO) for its high energy requirements. The heart disease observed in patients with a genetic defect in this pathway highlights the importance of FAO for cardiac health. We show that the consequences of a FAO defect extend beyond cardiac energy homeostasis and include amino acid metabolism and associated signaling pathways such as the integrated stress response.

Keywords:  LCAD; amino acids; fatty acid oxidation; hypertrophy; tRNA

DOI:  https://doi.org/10.1093/cvr/cvac050
Am J Ther. 2021 Nov 24. 29(2): e199-e204

Sodium-Glucose Cotransporter Inhibitors Reduce Mortality and Morbidity in Patients With Heart Failure: Evidence From a Meta-Analysis of Randomized Trials.

Massimiliano Camilli, Marco Lombardi, Juan G Chiabrando, Andrea Zito, Marco G Del Buono, Rocco Vergallo, Nadia Aspromonte, Antonella Lombardo, Rocco A Montone, Giampaolo Niccoli, Giuseppe Biondi-Zoccai, Filippo Crea, Giorgio Minotti.

BACKGROUND: Recent trials demonstrated the clinical efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with heart failure (HF), regardless of the presence or absence of type 2 diabetes. These data may allow the use of this innovative drug class in clinical routine for treating these patients.
STUDY QUESTION: We aimed at further clarifying the role of SGLT2i in patients with diagnosis of HF, capitalizing on pooled sample size and heightened power for clinically relevant safety and efficacy outcomes.
DATA SOURCES: We conducted a systematic search of PubMed, reference lists of relevant articles, and Medline database from inception until March 1, 2021.
STUDY DESIGN: This meta-analysis was completed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched for randomized trials that evaluated the cardiovascular effects of SGLT2i in patients with HF. Three investigators independently assessed study eligibility, extracted the data, and assessed risk of bias. Hazard ratios and 95% confidence intervals (CIs) were pooled and meta-analyzed using a random-effect model. Numbers needed to treat (NNT) with the relative 95% CIs were also calculated. The primary outcome was a composite of HF hospitalization or an urgent visit for worsening HF and cardiovascular death.
RESULTS: Three trials were included in the study. Overall, treatment with SGLT2i was associated with a lower risk of the primary composite outcome [hazard ratios 0.73, 95% CI (0.67-0.80), NNT = 11.3]. Similarly, there was a significantly reduced risk of cardiovascular death, all-cause death, HF hospitalization and need for urgent treatment for HF, and HF hospitalization.
CONCLUSIONS: Therefore, the available evidence supports the routine use of these drugs as standard-of-care, also given the highly favorable NNTs.

DOI: https://doi.org/10.1097/MJT.0000000000001452
Front Pharmacol. 2022 ;13 856386

An Effective Sodium-Dependent Glucose Transporter 2 Inhibition, Canagliflozin, Prevents Development of Hypertensive Heart Failure in Dahl Salt-Sensitive Rats.

Lili He, Sai Ma, Qingjuan Zuo, Guorui Zhang, Zhongli Wang, Tingting Zhang, Jianlong Zhai, Yifang Guo.

  Background: The aim of the study was to investigate the protective effect of canagliflozin (CANA) on myocardial metabolism and heart under stress overload and to further explore its possible molecular mechanism. Methods: High-salt diet was used to induce heart failure with preserved ejection fraction (HFpEF), and then, the physical and physiological indicators were measured. The cardiac function was evaluated by echocardiography and related indicators. Masson trichrome staining, wheat germ agglutinin, and immunohistochemical staining were conducted for histology analysis. Meanwhile, oxidative stress and cardiac ATP production were also determined. PCR and Western blotting were used for quantitative detection of related genes and proteins. Comprehensive metabolomics and proteomics were employed for metabolic analysis and protein expression analysis. Results: In this study, CANA showed diuretic, hypotensive, weight loss, and increased intake of food and water. Dahl salt-sensitive (DSS) rats fed with a diet containing 8% NaCl AIN-76A developed left ventricular remodeling and diastolic dysfunction caused by hypertension. After CANA treatment, cardiac hypertrophy and fibrosis were reduced, and the left ventricular diastolic function was improved. Metabolomics and proteomics data confirmed that CANA reduced myocardial glucose metabolism and increased fatty acid metabolism and ketogenesis in DSS rats, normalizing myocardial metabolism and reducing the myocardial oxidative stress. Mechanistically, CANA upregulated p-adenosine 5'-monophosphate-activated protein kinase (p-AMPK) and sirtuin 1 (SIRT1) and significantly induced the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a). Conclusion: CANA can improve myocardial hypertrophy, fibrosis, and left ventricular diastolic dysfunction induced by hypertension in DSS rats, possibly through the activation of the AMPK/SIRT1/PGC-1a pathway to regulate energy metabolism and oxidative stress.

Keywords:  canagliflozin; fibrosis; heart failure with preserved ejection fraction; hypertension; metabolism; myocardial hypertrophy

DOI:  https://doi.org/10.3389/fphar.2022.856386
Cell Metab. 2022 Apr 05. pii: S1550-4131(22)00096-1. [Epub ahead of print]34(4): 513-515

Ketones regulate endothelial homeostasis.

Gary D Lopaschuk, David A Hess, Subodh Verma.

In a recent paper in EMBO Molecular Medicine, Weis et al. reveal that cardiac endothelial cells can oxidize ketone bodies, which enhances cell proliferation, migration, and vessel sprouting. Furthermore, increasing ketone body levels with a ketogenic diet can increase endothelial cell proliferation and prevent blood vessel rarefication in hypertrophied mouse hearts. This suggests that increasing endothelial cell ketone oxidation has potential in treating heart failure.

DOI: https://doi.org/10.1016/j.cmet.2022.03.008
Front Endocrinol (Lausanne). 2022 ;13 802992

Comparative Cardiovascular Outcomes of SGLT2 Inhibitors in Type 2 Diabetes Mellitus: A Network Meta-Analysis of Randomized Controlled Trials.

Yu Jiang, Pingping Yang, Linghua Fu, Lizhe Sun, Wen Shen, Qinghua Wu.

   Background: A network meta-analysis of randomized controlled trials (RCTs) was conducted to explore the cardiovascular outcomes of all the kind and dosages of sodium-glucose cotransport-2 (SGLT2) inhibitors in type 2 diabetes mellitus (T2DM) patients.
Method and Result: The Cochrane Library, PubMed, and Embase databases were systematically searched for studies to compare the therapeutic effects of different SGLT2 inhibitors in T2DM patients. The effect measurements estimate chosen were odds ratios (ORs) and their corresponding 95% confidence interval (CI). Forty-seven RCTs involving a total of 70574 participants were eligible for direct and indirect comparisons. In direct comparison, treatment with dapagliflozin 5mg showed significantly lower risk of all-cause mortality compared with treatment with dapagliflozin 2.5mg (OR 0.09, 95% CI 0.01-0.70). According to NMA, interestingly, empagliflozin 10mg/25mg, and canagliflozin 100mg was associated with significantly lower risks of all-cause mortality compared with placebo (OR of 0.70, 95% CI 0.58-0.85; 0.69, 95% CI 0.57-0.84; and 0.83, 95% CI 0.73-0.95, respectively). Compared with placebo, dapagliflozin 10mg, empagliflozin 10mg and 25mg displayed the lower risks for cardiovascular events (OR 0.78, 95% CI 0.44-1.00; OR 0.47, 95% CI 0.22-0.93; and 0.43, 95% CI 0.24-0.74, respectively) by direct comparison. Moreover, canagliflozin 100/300mg showed significantly higher risks of cardiovascular events compared with empagliflozin 10mg (OR of 4.83, 95% CI 1.14-20.46 and 5.31, 95% CI 1.26-22.34, respectively) and empagliflozin 25mg (4.23, 95% CI 1.13-15.83 and 4.65, 95% CI 1.25-17.27, respectively) according to NMA. There were non-significant differences among all interventions in volume depletion in traditional pairwise meta-analysis. While in NMA, canagliflozin 100/300mg were associated with significantly increased risks of volume depletion compared with placebo (OR of 1.47, 95% CI 1.08-1.99 and 2.19, 95% CI 1.66-2.90, respectively).
Conclusion: In the limitations of the NMA, this study showed that empagliflozin might be better than other SGLT2 inhibitors with low risks of all-cause mortality and cardiovascular events in patients with T2DM suggesting the need for ad hoc RCTs.

Keywords:  SGLT2 inhibitors; cardiovascular events; empagliflozin; meta-analysis; type 2 diabetes mellitus

DOI:  https://doi.org/10.3389/fendo.2022.802992