bims-hafaim 2023-07-09 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2023–07–09
ten papers selected by
Kyle McCommis, Saint Louis University

Effect of SH2B1 on glucose metabolism during pressure overload-induced cardiac hypertrophy and cardiac dysfunction.
Association of Carbohydrate Antigen 125 on the Response to Dapagliflozin in Patients With Heart Failure.
Identify Tcea3 as a novel anti-cardiomyocyte hypertrophy gene involved in fatty acid oxidation and oxidative stress.
Cardiac lipid metabolism, mitochondrial function and heart failure.
Efficacy of SGLT2-inhibitors across different definitions of heart failure with preserved ejection fraction.
Novel insights into the role of mitochondria in diabetic cardiomyopathy: molecular mechanisms and potential treatments.
Ketogenic Diet in Heart Failure: Fact or Fiction?
Ferroptosis in mitochondrial cardiomyopathy.
Postmortem diagnosis of very long chain acyl-CoA dehydrogenase (VLCAD) deficiency in a neonate with sudden cardiac death.
Glucagon-like peptide-1 receptor agonists across the spectrum of heart failure.

Clin Exp Pharmacol Physiol. 2023 Jul 03.

Effect of SH2B1 on glucose metabolism during pressure overload-induced cardiac hypertrophy and cardiac dysfunction.

Beilei Liu, Xuguang Liu, Shan Hu, Shuai Mao, Manqi Yang, Bin Wu, Gang Wu.

  This study mainly explored the effect and mechanism of Src homology 2 (SH2) B adaptor protein 1 (SH2B1) on cardiac glucose metabolism during pressure overload-induced cardiac hypertrophy and dysfunction. A pressure-overloaded cardiac hypertrophy model was constructed, and SH2B1-siRNA was injected through the tail vein. Haematoxylin and eosin (H&E) staining was used to detect myocardial morphology. ANP, BNP, β-MHC and the diameter of myocardial fibres were quantitatively measured to evaluate the degree of cardiac hypertrophy, respectively. GLUT1, GLUT4, and IR were detected to assess cardiac glucose metabolism. Cardiac function was determined by echocardiography. Then, glucose oxidation and uptake, glycolysis and fatty acid metabolism were assessed in Langendorff perfusion of hearts. Finally, PI3K/AKT activator was used to further explore the relevant mechanism. The results showed that during cardiac pressure overload, with the aggravation of cardiac hypertrophy and dysfunction, cardiac glucose metabolism and glycolysis increased, and fatty acid metabolism decreased. After SH2B1-siRNA transfection, cardiac SH2B1 expression was knocked down, and the degree of cardiac hypertrophy and dysfunction was alleviated compared with the Control-siRNA transfected group. Simultaneously, cardiac glucose metabolism and glycolysis were reduced, and fatty acid metabolism was enhanced. The SH2B1 expression knockdown mitigated the cardiac hypertrophy and dysfunction by reducing cardiac glucose metabolism. After using PI3K/AKT activator, the effect of SH2B1 expression knockdown on cardiac glucose metabolism was reversed during cardiac hypertrophy and dysfunction. Collectively, SH2B1 regulated cardiac glucose metabolism by activating the PI3K/AKT pathway during pressure overload-induced cardiac hypertrophy and cardiac dysfunction.

Keywords:  PI3K/AKT; SH2B1; cardiac hypertrophy; glucose metabolism

DOI:  https://doi.org/10.1111/1440-1681.13807
J Am Coll Cardiol. 2023 07 11. pii: S0735-1097(23)05589-4. [Epub ahead of print]82(2): 142-157

Association of Carbohydrate Antigen 125 on the Response to Dapagliflozin in Patients With Heart Failure.

Kieran F Docherty, Kirsty McDowell, Paul Welsh, Joanna Osmanska, Inder Anand, Rudolf A de Boer, Lars Køber, Mikhail N Kosiborod, Felipe A Martinez, Eileen O'Meara, Piotr Ponikowski, Morten Schou, David D Berg, Marc S Sabatine, David A Morrow, Petr Jarolim, Ann Hammarstedt, Mikaela Sjöstrand, Anna Maria Langkilde, Scott D Solomon, Naveed Sattar, Pardeep S Jhund, John J V McMurray.

   BACKGROUND: Elevated circulating carbohydrate antigen 125 (CA125) is a marker of congestion and a predictor of outcomes in acute heart failure (HF). Less is known about CA125 in chronic ambulatory HF with reduced ejection fraction.
OBJECTIVES: This study examined the association between baseline CA125 (and changes in CA125) and outcomes in patients with HF with reduced ejection fraction in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; NCT03036124) trial and its relationship with the effect of dapagliflozin.
METHODS: The primary outcome was a composite of a first episode of worsening HF or cardiovascular death. CA125 was measured at baseline and 12 months following randomization.
RESULTS: Median baseline CA125 was 13.04 U/mL (IQR: 8.78-21.13 U/mL) in 3,123 of 4,774 patients with available data. Compared with CA125 ≤35 U/mL (upper limit of normal), patients with CA125 >35 U/mL were at a higher risk of the primary outcome (adjusted HR: 1.59; 95% CI: 1.29-1.96). The adjusted risks of the primary outcome relative to quartile 1 (Q1) (≤8.78 U/mL) were as follow: Q2, 8.79-13.04 U/mL (HR: 0.94; 95% CI: 0.71-1.24); Q3, 13.05-21.13 U/mL (HR: 1.22; 95% CI: 0.94-1.59); Q4, ≥21.14 U/mL (HR: 1.63; 95% CI: 1.28-2.09). The beneficial effect of dapagliflozin compared with placebo on the primary outcome was consistent whether CA125 was analyzed in quartiles (interaction P = 0.13) or as a continuous variable (interaction P = 0.75). The placebo-corrected relative change in CA125 at 12 months was -5.2% (95% CI: -10.6% to 0.5%; P = 0.07).
CONCLUSIONS: In DAPA-HF, elevated CA125 levels were an independent predictor of the risk of worsening HF or cardiovascular death. Dapagliflozin reduced the risk of worsening HF or cardiovascular death regardless of baseline CA125.

Keywords:  CA125; SGLT2 inhibitor; congestion; heart failure

DOI:  https://doi.org/10.1016/j.jacc.2023.05.011
Front Cardiovasc Med. 2023 ;10 1137429

Identify Tcea3 as a novel anti-cardiomyocyte hypertrophy gene involved in fatty acid oxidation and oxidative stress.

Yingying Guo, Xian-Feng Cen, Dan Li, Hong-Liang Qiu, Ya-Jie Chen, Meng Zhang, Si-Hui Huang, Hao Xia, Man Xu.

   Background: Chronic pressure overload triggers pathological cardiac hypertrophy that eventually leads to heart failure. Effective biomarkers and therapeutic targets for heart failure remain to be defined. The aim of this study is to identify key genes associated with pathological cardiac hypertrophy by combining bioinformatics analyses with molecular biology experiments.
Methods: Comprehensive bioinformatics tools were used to screen genes related to pressure overload-induced cardiac hypertrophy. We identified differentially expressed genes (DEGs) by overlapping three Gene Expression Omnibus (GEO) datasets (GSE5500, GSE1621, and GSE36074). Correlation analysis and BioGPS online tool were used to detect the genes of interest. A mouse model of cardiac remodeling induced by transverse aortic constriction (TAC) was established to verify the expression of the interest gene during cardiac remodeling by RT-PCR and western blot. By using RNA interference technology, the effect of transcription elongation factor A3 (Tcea3) silencing on PE-induced hypertrophy of neonatal rat ventricular myocytes (NRVMs) was detected. Next, gene set enrichment analysis (GSEA) and the online tool ARCHS4 were used to predict the possible signaling pathways, and the fatty acid oxidation relevant pathways were enriched and then verified in NRVMs. Furthermore, the changes of long-chain fatty acid respiration in NRVMs were detected using the Seahorse XFe24 Analyzer. Finally, MitoSOX staining was used to detect the effect of Tcea3 on mitochondrial oxidative stress, and the contents of NADP(H) and GSH/GSSG were detected by relevant kits.
Results: A total of 95 DEGs were identified and Tcea3 was negatively correlated with Nppa, Nppb and Myh7. The expression level of Tcea3 was downregulated during cardiac remodeling both in vivo and in vitro. Knockdown of Tcea3 aggravated cardiomyocyte hypertrophy induced by PE in NRVMs. GSEA and online tool ARCHS4 predict Tcea3 involved in fatty acid oxidation (FAO). Subsequently, RT-PCR results showed that knockdown of Tcea3 up-regulated Ces1d and Pla2g5 mRNA expression levels. In PE induced cardiomyocyte hypertrophy, Tcea3 silencing results in decreased fatty acid utilization, decreased ATP synthesis and increased mitochondrial oxidative stress.
Conclusion: Our study identifies Tcea3 as a novel anti-cardiac remodeling target by regulating FAO and governing mitochondrial oxidative stress.

Keywords:  Tcea3; bioinformatics; fatty acid oxidation; heart failure; transcriptional regulator

DOI:  https://doi.org/10.3389/fcvm.2023.1137429
Cardiovasc Res. 2023 Jul 01. pii: cvad100. [Epub ahead of print]

Cardiac lipid metabolism, mitochondrial function and heart failure.

Lorenzo Da Dalt, Ainara G Cabodevilla, Ira J Goldberg, Giuseppe Danilo Norata.

  A fine balance between uptake, storage and the use of high energy fuels, like lipids, is crucial in the homeostasis of different metabolic tissues. Nowhere is this balance more important and more precarious than in the heart. This highly energy demanding muscle normally oxidizes almost all the available substrates to generate energy, with fatty acids being the preferred source under physiological conditions. In patients with cardiomyopathies and heart failure, changes in the main energetic substrate are observed; these hearts often prefer to utilize glucose rather than oxidizing fatty acids. An imbalance between uptake and oxidation of fatty acid can result in cellular lipid accumulation and cytotoxicity. In this review we will focus on the sources and uptake pathways used to direct fatty acids to cardiomyocytes. We will then discuss the intracellular machinery used to either store or oxidize these lipids and explain how disruptions in homeostasis can lead to mitochondrial dysfunction and heart failure. Moreover, we will also discuss the role of cholesterol accumulation in cardiomyocytes. Our discussion will attempt to weave in vitro experiments and in vivo data from mice and humans and use several human diseases to illustrate metabolism gone haywire as a cause of or accomplice to cardiac dysfunction.

Keywords:  Cholesterol and Heart failure; Lipids; Lipoprotein

DOI:  https://doi.org/10.1093/cvr/cvad100
J Cardiovasc Med (Hagerstown). 2023 08 01. 24(8): 537-543

Efficacy of SGLT2-inhibitors across different definitions of heart failure with preserved ejection fraction.

Vincenzo De Marzo, Gianluigi Savarese, Italo Porto, Marco Metra, Pietro Ameri.

AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been evaluated in phase 3 randomized-controlled trials (RCTs) that enrolled individuals with heart failure and preserved ejection fraction (HFpEF) based on detailed clinical, biochemical, and echocardiographic criteria (hereafter HF-RCTs), and in cardiovascular outcomes trials (CVOTs) in diabetic patients, in which the diagnosis of HFpEF relied on medical history.
METHODS AND RESULTS: We performed a study-level meta-analysis of the efficacy of SGLT2i across different definitions of HFpEF. Three HF-RCTs (EMPEROR-Preserved, DELIVER, and SOLOIST-WHF) and four CVOTs (EMPA-REG OUTCOME, DECLARE-TIMI 58, VERTIS-CV, and SCORED) were included, for a total of 14 034 patients. SGLT2i reduced the risk of cardiovascular death or heart failure hospitalization (HFH) in all RCTs pooled together [risk ratio 0.75, 95% confidence interval (95% CI) 0.63-0.89, NNT 19], in HF-RCTs (risk ratio 0.71, 95% CI 0.52-0.97, NNT 13), and in CVOTs (risk ratio 0.78, 95% CI 0.60-0.99, NNT 26). SGLT2i also decreased the risk of HFH in all RCTs (risk ratio 0.81, 95% CI 0.73-0.90, NNT 45), in HF-RCTs (risk ratio 0.81, 95% CI 0.72-0.93, NNT 37), and in CVOTs (risk ratio 0.78, 95% CI 0.61-0.99, NNT 46). By contrast, SGLT2i were not superior to placebo for cardiovascular death or all-cause death in all RCTs, HF-RCTs, or CVOTs. Results were comparable after excluding one RCT at a time. Meta-regression analysis confirmed that the type of RCT (HF-RCT vs. CVOT) did not influence the SGLT2i effect.
CONCLUSIONS: In RCTs, SGLT2i improved the outcomes of patients with HFpEF regardless of how the latter was diagnosed.

DOI: https://doi.org/10.2459/JCM.0000000000001504
Cell Stress Chaperones. 2023 Jul 05.

Novel insights into the role of mitochondria in diabetic cardiomyopathy: molecular mechanisms and potential treatments.

Fumin Zhi, Qian Zhang, Li Liu, Xing Chang, Hongtao Xu.

  Diabetic cardiomyopathy describes decreased myocardial function in diabetic patients in the absence of other heart diseases such as myocardial ischemia and hypertension. Recent studies have defined numerous molecular interactions and signaling events that may account for deleterious changes in mitochondrial dynamics and functions influenced by hyperglycemic stress. A metabolic switch from glucose to fatty acid oxidation to fuel ATP synthesis, mitochondrial oxidative injury resulting from increased mitochondrial ROS production and decreased antioxidant capacity, enhanced mitochondrial fission and defective mitochondrial fusion, impaired mitophagy, and blunted mitochondrial biogenesis are major signatures of mitochondrial pathologies during diabetic cardiomyopathy. This review describes the molecular alterations underlying mitochondrial abnormalities associated with hyperglycemia and discusses their influence on cardiomyocyte viability and function. Based on basic research findings and clinical evidence, diabetic treatment standards and their impact on mitochondrial function, as well as mitochondria-targeted therapies of potential benefit for diabetic cardiomyopathy patients, are also summarized.

Keywords:  Diabetic cardiomyopathy; Mitochondria; Mitochondrial biogenesis; Mitochondrial fission/fusion; Mitochondrial metabolism; Mitochondrial oxidative stress; Mitophagy

DOI:  https://doi.org/10.1007/s12192-023-01361-w
JACC Heart Fail. 2023 07;pii: S2213-1779(23)00241-X. [Epub ahead of print]11(7): 838-844

Ketogenic Diet in Heart Failure: Fact or Fiction?

Nandan Kodur, Salva Yurista, Valesha Province, Emma Rueth, Christopher Nguyen, W H Wilson Tang.



Keywords:  heart failure; ketogenic diet; ketone bodies

DOI:  https://doi.org/10.1016/j.jchf.2023.05.009
Trends Cell Biol. 2023 Jul 05. pii: S0962-8924(23)00125-3. [Epub ahead of print]

Ferroptosis in mitochondrial cardiomyopathy.

Sofia Ahola, Thomas Langer.

  Ferroptosis is a form of necrotic cell death characterized by iron-dependent lipid peroxidation culminating in membrane rupture. Accumulating evidence links ferroptosis to multiple cardiac diseases and identifies mitochondria as important regulators of ferroptosis. Mitochondria are not only a major source of reactive oxygen species (ROS) but also counteract ferroptosis by preserving cellular redox balance and oxidative defense. Recent evidence has revealed that the mitochondrial integrated stress response limits oxidative stress and ferroptosis in oxidative phosphorylation (OXPHOS)-deficient cardiomyocytes and protects against mitochondrial cardiomyopathy. We summarize the multiple ways in which mitochondria modulate the susceptibility of cells to ferroptosis, and discuss the implications of ferroptosis for cardiomyopathies in mitochondrial disease.

Keywords:  Gpx4; ferroptosis; integrated stress response; mitochondrial cardiomyopathy

DOI:  https://doi.org/10.1016/j.tcb.2023.06.002
JIMD Rep. 2023 Jul;64(4): 261-264

Postmortem diagnosis of very long chain acyl-CoA dehydrogenase (VLCAD) deficiency in a neonate with sudden cardiac death.

Prapti Singh, Deirdre Amaro, Olugbemisola Obi, Fnu Kiran, Erin Hediger, Tomi L Toler, Patricia I Dickson, Dorothy K Grange.

  Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is an autosomal recessive long chain fatty acid β-oxidation disorder with a variable clinical spectrum, ranging from an acute neonatal presentation with cardiac and hepatic failure to childhood or adult onset of symptoms with hepatomegaly or rhabdomyolysis provoked by illness or exertion. Neonatal cardiac arrest or sudden unexpected death can be the presenting phenotype in some patients, emphasizing the importance of early clinical suspicion and intervention. We report a patient who had a cardiac arrest and died at one day of age. Following her death, the newborn screen reported biochemical evidence of VLCAD deficiency, which was confirmed with pathologic findings at autopsy and by molecular genetic testing.

Keywords:  cardiac arrest; newborn screening; very long chain acyl CoA dehydrogenase (VLCAD) deficiency

DOI:  https://doi.org/10.1002/jmd2.12365
J Clin Endocrinol Metab. 2023 Jul 06. pii: dgad398. [Epub ahead of print]

Glucagon-like peptide-1 receptor agonists across the spectrum of heart failure.

João Pedro Ferreira, Abhinav Sharma, Javed Butler, Milton Packer, Faiez Zannad, Francisco Vasques-Nóvoa, Adelino Leite-Moreira, João Sérgio Neves.

  Glucagon-like peptide-1 receptor agonists (GLP-1 RA) have been used to reduce body weight in overweight or people with obesity and to improve glycemic control and cardiovascular outcomes among people with type 2 diabetes (T2D) and a high cardiovascular risk. However, the effects of GLP-1 RA may be modified by the presence of heart failure (HF). In this review, we summarize the evidence for the use of GLP-1 RA across patient's risk with a particular focus in HF. After a careful review of the literature, we challenge the current views about the use of GLP-1 RA and suggest performing an active HF screening (with directed clinical history, physical examination, an echocardiogram, and natriuretic peptides) before initiating a GLP-1 RA. After HF screening, we suggest GLP-1 RA treatment decisions as follows: 1) in people with T2D without HF, GLP-1 RA should be used for reducing the risk of myocardial infarction and stroke, with a possible effect to reduce the risk of heart failure hospitalizations; 2) in patients with a heart failure and preserved ejection fraction (HFpEF), GLP-1 RA do not reduce HF hospitalizations but may reduce atherosclerotic events, and their use may be considered in an individualized manner; and 3) in patients with heart failure and reduced ejection fraction (HFrEF), the use of GLP-1RA warrants caution due to potential risk of worsening HF events and arrhythmias, pending risk-benefit data from further studies.

Keywords:  Glucagon-like peptide-1 receptor agonists; Heart failure; Risk modification

DOI:  https://doi.org/10.1210/clinem/dgad398